The Experts below are selected from a list of 20682 Experts worldwide ranked by ideXlab platform

Eisei Sohara - One of the best experts on this subject based on the ideXlab platform.

  • Renal TNFα activates the WNK Phosphorylation Cascade and contributes to salt-sensitive hypertension in chronic kidney disease
    Kidney international, 2020
    Co-Authors: Taisuke Furusho, Eisei Sohara, Shintaro Mandai, Hiroaki Kikuchi, Naohiro Takahashi, Takuya Fujimaru, Hiroko Hashimoto, Yohei Arai, Fumiaki Ando, Moko Zeniya
    Abstract:

    The inappropriate over-activation of the with-no-lysine kinase (WNK)–STE20/SPS1–related proline/alanine-rich kinase (SPAK)–sodium chloride cotransporter (NCC) Phosphorylation Cascade increases sodium reabsorption in distal kidney nephrons, resulting in salt-sensitive hypertension. Although chronic kidney disease (CKD) is a common cause of salt-sensitive hypertension, the involvement of the WNK Phosphorylation Cascade is unknown. Moreover, the effect of immune systems on WNK kinases has not been investigated despite the fact that immune systems are important for salt sensitivity. Here we demonstrate that the protein abundance of WNK1, but not of WNK4, was increased at the distal convoluted tubules in the aristolochic acid nephropathy mouse model of CKD. Accordingly, the Phosphorylation of both SPAK and NCC was also increased. Moreover, a high-salt diet did not adequately suppress activation of the WNK1–SPAK–NCC Phosphorylation Cascade in this model, leading to salt-sensitive hypertension. WNK1 also was increased in adenine nephropathy, but not in subtotal nephrectomy, models of CKD. By comparing the transcripts of these three models focusing on immune systems, we hypothesized that tumor necrosis factor (TNF)-α regulates WNK1 protein expression. In fact, TNF-α increased WNK1 protein expression in cultured renal tubular cells by reducing the transcription and protein levels of NEDD4-2 E3-ligase, which degrades WNK1 protein. Furthermore, the TNF-α inhibitor etanercept reversed the reduction of NEDD4-2 expression and upregulation of the WNK1–SPAK–NCC Phosphorylation Cascade in distal convoluted tubules in vivo in the aristolochic acid nephropathy model. Thus, salt-sensitive hypertension is induced in CKD via activation of the renal WNK1– SPAK–NCC Phosphorylation Cascade by TNF-α, reflecting a link with the immune system.

  • impaired degradation of wnk1 and wnk4 kinases causes phaii in mutant klhl3 knock in mice
    Human Molecular Genetics, 2014
    Co-Authors: Koichiro Susa, Moko Zeniya, Hidenori Nishida, Daiei Takahashi, Motoko Chiga, Naohiro Nomura, Yutaro Mori, Takayasu Mori, Eisei Sohara, Kiyoshi Isobe
    Abstract:

    Pseudohypoaldosteronism type II (PHAII) is a hereditary disease characterized by salt-sensitive hypertension, hyperkalemia and metabolic acidosis, and genes encoding with-no-lysine kinase 1 (WNK1) and WNK4 kinases are known to be responsible. Recently, Kelch-like 3 (KLHL3) and Cullin3, components of KLHL3-Cullin3 E3 ligase, were newly identified as responsible for PHAII. We have reported that WNK4 is the substrate of KLHL3Cullin3 E3 ligase-mediated ubiquitination. However, WNK1 and Na‐Cl cotransporter (NCC) were also reported tobeasubstrateofKLHL3-Cullin3E3ligasebyothergroups.Therefore,itremainsunclearwhichmoleculeisthe target(s)ofKLHL3.ToinvestigatethepathogenesisofPHAIIcausedbyKLHL3mutation,wegeneratedandanalyzedKLHL3 R528H/1 knock-inmice.KLHL3 R528H/1 knock-inmiceexhibitedsalt-sensitivehypertension,hyperkalemiaandmetabolicacidosis.Moreover,thePhosphorylationofNCCwasincreasedintheKLHL3 R528H/1 mouse kidney,indicatingthattheKLHL3 R528H/1 knock-inmouseisanidealmousemodelofPHAII.Interestingly,theprotein expression of both WNK1 and WNK4 was significantly increased in the KLHL3 R528H/1 mouse kidney, confirming that increases in these WNK kinases activated the WNK-OSR1/SPAK-NCC Phosphorylation Cascade in KLHL3 R528H/1 knock-in mice. To examine whether mutant KLHL3 R528H can interact with WNK kinases, we measuredthebindingofTAMRA-labeledWNK1andWNK4peptidestofull-lengthKLHL3usingfluorescencecor

  • dietary salt intake regulates wnk3 spak nkcc1 Phosphorylation Cascade in mouse aorta through angiotensin ii
    Hypertension, 2013
    Co-Authors: Moko Zeniya, Daiei Takahashi, Koichiro Susa, Motoko Chiga, Takayasu Mori, Eisei Sohara, Satomi Kita, Takahiro Iwamoto, Sung-sen Yang, Shihhua Lin
    Abstract:

    Na-K-Cl cotransporter isoform 1 (NKCC1) is involved in the regulation of vascular smooth muscle cell contraction. Recently, the with-no-lysine kinase (WNK)-STE20/SPS1-related proline/alanine-rich kinase (SPAK)-NKCC1 Phosphorylation Cascade in vascular smooth muscle cells was found to be important in the regulation of vascular tone. In this study, we investigated whether the WNK-SPAK-NKCC1 Cascade in mouse aortic tissue is regulated by dietary salt intake and the mechanisms responsible. Phosphorylation of SPAK and NKCC1 was significantly reduced in the aorta in high-salt-fed mice and was increased in the aorta in low-salt-fed mice, indicating that the WNK-SPAK-NKCC1 Phosphorylation Cascade in the aorta was indeed regulated by dietary salt intake. Acute and chronic angiotensin II infusion increased Phosphorylation of SPAK and NKCC1 in the mouse aorta. In addition, valsartan, an antagonist of angiotensin II type 1 receptor, inhibited low-salt diet-induced Phosphorylation of SPAK and NKCC1, demonstrating that angiotensin II activates the WNK-SPAK-NKCC1 Phosphorylation Cascade through the angiotensin II type 1 receptor. However, a low-salt diet and angiotensin II together did not increase Phosphorylation of SPAK and NKCC1 in the aorta in WNK3 knockout mice, indicating that activation of the WNK-SPAK-NKCC1 Phosphorylation Cascade induced by a low-salt diet and angiotensin II is dependent on WNK3. Indeed, angiotensin II-induced increases in blood pressure were diminished in WNK3 knockout mice. In addition, decreased response to angiotensin II in the mesenteric arteries was observed in WNK3 knockout mice. Our data also clarified a novel mechanism for regulation of vascular tonus by angiotensin II. Inhibition of this Cascade could, therefore, be a novel therapeutic target in hypertension.

  • Dietary Salt Intake Regulates WNK3–SPAK–NKCC1 Phosphorylation Cascade in Mouse Aorta Through Angiotensin II
    Hypertension (Dallas Tex. : 1979), 2013
    Co-Authors: Moko Zeniya, Daiei Takahashi, Koichiro Susa, Motoko Chiga, Takayasu Mori, Eisei Sohara, Satomi Kita, Takahiro Iwamoto, Sung-sen Yang
    Abstract:

    Na-K-Cl cotransporter isoform 1 (NKCC1) is involved in the regulation of vascular smooth muscle cell contraction. Recently, the with-no-lysine kinase (WNK)-STE20/SPS1-related proline/alanine-rich kinase (SPAK)-NKCC1 Phosphorylation Cascade in vascular smooth muscle cells was found to be important in the regulation of vascular tone. In this study, we investigated whether the WNK-SPAK-NKCC1 Cascade in mouse aortic tissue is regulated by dietary salt intake and the mechanisms responsible. Phosphorylation of SPAK and NKCC1 was significantly reduced in the aorta in high-salt-fed mice and was increased in the aorta in low-salt-fed mice, indicating that the WNK-SPAK-NKCC1 Phosphorylation Cascade in the aorta was indeed regulated by dietary salt intake. Acute and chronic angiotensin II infusion increased Phosphorylation of SPAK and NKCC1 in the mouse aorta. In addition, valsartan, an antagonist of angiotensin II type 1 receptor, inhibited low-salt diet-induced Phosphorylation of SPAK and NKCC1, demonstrating that angiotensin II activates the WNK-SPAK-NKCC1 Phosphorylation Cascade through the angiotensin II type 1 receptor. However, a low-salt diet and angiotensin II together did not increase Phosphorylation of SPAK and NKCC1 in the aorta in WNK3 knockout mice, indicating that activation of the WNK-SPAK-NKCC1 Phosphorylation Cascade induced by a low-salt diet and angiotensin II is dependent on WNK3. Indeed, angiotensin II-induced increases in blood pressure were diminished in WNK3 knockout mice. In addition, decreased response to angiotensin II in the mesenteric arteries was observed in WNK3 knockout mice. Our data also clarified a novel mechanism for regulation of vascular tonus by angiotensin II. Inhibition of this Cascade could, therefore, be a novel therapeutic target in hypertension.

  • pi3k akt signaling pathway activates the wnk osr1 spak ncc Phosphorylation Cascade in hyperinsulinemic db db mice
    Hypertension, 2012
    Co-Authors: Hidenori Nishida, Motoko Chiga, Naohiro Nomura, Eisei Sohara, Dario R. Alessi, Tatemitsu Rai, Sei Sasaki, Shinichi Uchida
    Abstract:

    Metabolic syndrome patients have insulin resistance, which causes hyperinsulinemia, which in turn causes aberrant increased renal sodium reabsorption. The precise mechanisms underlying this greater salt-sensitivity of hyperinsulinemic patients remain unclear. Abnormal activation of the recently-identified WNK kinase-OSR1/SPAK kinases-NCC transporter Phosphorylation Cascade results in the salt-sensitive hypertension of pseudohypoaldosteronism type II. Here, we report a study of renal WNK-OSR1/SPAK-NCC Cascade activation in the db/db mouse model of hyperinsulinemic metabolic syndrome. Thiazide sensitivity was increased, suggesting greater activity of NCC in db/db mice. In fact, increased Phosphorylation of OSR1/SPAK and NCC was observed. In both SpakT243A/+ and Osr1T185A/+ knock-in db/db mice, which carry mutations that disrupt the signal from WNK kinases, increased Phosphorylation of NCC and elevated blood pressure were completely corrected, indicating that Phosphorylation of SPAK and OSR1 by WNK kinases is required for the increased activation and Phosphorylation of NCC in this model. Renal phosphorylated Akt was increased in db/db mice, suggesting that increased NCC Phosphorylation is regulated by the PI3K/Akt signaling Cascade in the kidney in response to hyperinsulinemia. A PI3K inhibitor (NVP-BEZ235) corrected the increased OSR1/SPAK-NCC Phosphorylation. Another more specific PI3K inhibitor (GDC-0941) and an Akt inhibitor (MK-2206) also inhibited increased NCC Phosphorylation. These results indicate that the PI3K/Akt signaling pathway activates the WNK-OSR1/SPAK-NCC Phosphorylation Cascade in db/db mice. This mechanism may play a role in the pathogenesis of salt-sensitive hypertension in human hyperinsulinemic conditions such as the metabolic syndrome.

Shinichi Uchida - One of the best experts on this subject based on the ideXlab platform.

  • Evaluation of Phosphorylated Urinary Na-Cl Cotransporter Is Potentially Useful in a Patient With Pseudohypoaldosteronism Type II due to Mutation in CUL3.
    Global Pediatric Health, 2014
    Co-Authors: Keiko Nagahara, Motoko Chiga, Kiyoshi Isobe, Shinichi Uchida, Yoshifusa Abe, Akira Hojo, Kazushige Dobashi, Kazuo Itabashi
    Abstract:

    Pseudohypoaldosteronism type II (PHA II), which is also known as Gordon syndrome, is a rare autosomal dominant disease characterized by hypertension, hyperkalemia, hyperchloremic metabolic acidosis, and the absence of hyponatremia and hyperaldosteronemia.1 The pathophysiology of PHA II is explained by the constitutive activation of WNK (with no lysine) kinases–OSR1/SPAK kinases–sodium/chloride cotransporter (NCC) Phosphorylation Cascade. NCC is distributed on the apical plasma membranes of the distal convoluted tubules, and activation of NCC mediates increasing sodium chloride (NaCl) reabsorption in the kidney, leading to hypertension, hyperkalemia, and metabolic acidosis.2 Mutations of 4 genes, WNK1, WNK4, KLHL3 (Kelch-like 3), and CUL3 (Cullin 3), have been reported to be responsible to PHA II.3,4 Here, we present the case of a 6-year-old Japanese boy with PHA II. Our case is the third one with novel mutation in CUL3 gene. We also studied the excretion of urinary total NCC (tNCC) and phosphorylated NCC (pNCC) in his family members.

  • pi3k akt signaling pathway activates the wnk osr1 spak ncc Phosphorylation Cascade in hyperinsulinemic db db mice
    Hypertension, 2012
    Co-Authors: Hidenori Nishida, Motoko Chiga, Naohiro Nomura, Eisei Sohara, Dario R. Alessi, Tatemitsu Rai, Sei Sasaki, Shinichi Uchida
    Abstract:

    Metabolic syndrome patients have insulin resistance, which causes hyperinsulinemia, which in turn causes aberrant increased renal sodium reabsorption. The precise mechanisms underlying this greater salt-sensitivity of hyperinsulinemic patients remain unclear. Abnormal activation of the recently-identified WNK kinase-OSR1/SPAK kinases-NCC transporter Phosphorylation Cascade results in the salt-sensitive hypertension of pseudohypoaldosteronism type II. Here, we report a study of renal WNK-OSR1/SPAK-NCC Cascade activation in the db/db mouse model of hyperinsulinemic metabolic syndrome. Thiazide sensitivity was increased, suggesting greater activity of NCC in db/db mice. In fact, increased Phosphorylation of OSR1/SPAK and NCC was observed. In both SpakT243A/+ and Osr1T185A/+ knock-in db/db mice, which carry mutations that disrupt the signal from WNK kinases, increased Phosphorylation of NCC and elevated blood pressure were completely corrected, indicating that Phosphorylation of SPAK and OSR1 by WNK kinases is required for the increased activation and Phosphorylation of NCC in this model. Renal phosphorylated Akt was increased in db/db mice, suggesting that increased NCC Phosphorylation is regulated by the PI3K/Akt signaling Cascade in the kidney in response to hyperinsulinemia. A PI3K inhibitor (NVP-BEZ235) corrected the increased OSR1/SPAK-NCC Phosphorylation. Another more specific PI3K inhibitor (GDC-0941) and an Akt inhibitor (MK-2206) also inhibited increased NCC Phosphorylation. These results indicate that the PI3K/Akt signaling pathway activates the WNK-OSR1/SPAK-NCC Phosphorylation Cascade in db/db mice. This mechanism may play a role in the pathogenesis of salt-sensitive hypertension in human hyperinsulinemic conditions such as the metabolic syndrome.

  • phosphatidylinositol 3 kinase akt signaling pathway activates the wnk osr1 spak ncc Phosphorylation Cascade in hyperinsulinemic db db micenovelty and significance
    Hypertension, 2012
    Co-Authors: Hidenori Nishida, Motoko Chiga, Naohiro Nomura, Eisei Sohara, Dario R. Alessi, Tatemitsu Rai, Sei Sasaki, Shinichi Uchida
    Abstract:

    Metabolic syndrome patients have insulin resistance, which causes hyperinsulinemia, which in turn causes aberrant increased renal sodium reabsorption. The precise mechanisms underlying this greater salt sensitivity of hyperinsulinemic patients remain unclear. Abnormal activation of the recently identified with-no-lysine kinase (WNK)-oxidative stress-responsive kinase 1 (OSR1)/STE20/SPS1-related proline/alanine-rich kinase (SPAK)-NaCl cotransporter (NCC) Phosphorylation Cascade results in the salt-sensitive hypertension of pseudohypoaldosteronism type II. Here, we report a study of renal WNK-OSR1/SPAK-NCC Cascade activation in the db/db mouse model of hyperinsulinemic metabolic syndrome. Thiazide sensitivity was increased, suggesting greater activity of NCC in db/db mice. In fact, increased Phosphorylation of OSR1/SPAK and NCC was observed. In both Spak T243A/+ and Osr1 T185A/+ knock-in db/db mice, which carry mutations that disrupt the signal from WNK kinases, increased Phosphorylation of NCC and elevated blood pressure were completely corrected, indicating that Phosphorylation of SPAK and OSR1 by WNK kinases is required for the increased activation and Phosphorylation of NCC in this model. Renal phosphorylated Akt was increased in db/db mice, suggesting that increased NCC Phosphorylation is regulated by the phosphatidylinositol 3-kinase/Akt signaling Cascade in the kidney in response to hyperinsulinemia. A phosphatidylinositol 3-kinase inhibitor (NVP-BEZ235) corrected the increased OSR1/SPAK-NCC Phosphorylation. Another more specific phosphatidylinositol 3-kinase inhibitor (GDC-0941) and an Akt inhibitor (MK-2206) also inhibited increased NCC Phosphorylation. These results indicate that the phosphatidylinositol 3-kinase/Akt signaling pathway activates the WNK-OSR1/SPAK-NCC Phosphorylation Cascade in db/db mice. This mechanism may play a role in the pathogenesis of salt-sensitive hypertension in human hyperinsulinemic conditions, such as the metabolic syndrome.

  • PI3K/Akt Signaling Pathway Activates the WNK-OSR1/SPAK-NCC Phosphorylation Cascade in Hyperinsulinemic db/db Mice
    Hypertension (Dallas Tex. : 1979), 2012
    Co-Authors: Hidenori Nishida, Motoko Chiga, Naohiro Nomura, Eisei Sohara, Dario R. Alessi, Tatemitsu Rai, Sei Sasaki, Shinichi Uchida
    Abstract:

    Metabolic syndrome patients have insulin resistance, which causes hyperinsulinemia, which in turn causes aberrant increased renal sodium reabsorption. The precise mechanisms underlying this greater salt-sensitivity of hyperinsulinemic patients remain unclear. Abnormal activation of the recently-identified WNK kinase-OSR1/SPAK kinases-NCC transporter Phosphorylation Cascade results in the salt-sensitive hypertension of pseudohypoaldosteronism type II. Here, we report a study of renal WNK-OSR1/SPAK-NCC Cascade activation in the db/db mouse model of hyperinsulinemic metabolic syndrome. Thiazide sensitivity was increased, suggesting greater activity of NCC in db/db mice. In fact, increased Phosphorylation of OSR1/SPAK and NCC was observed. In both SpakT243A/+ and Osr1T185A/+ knock-in db/db mice, which carry mutations that disrupt the signal from WNK kinases, increased Phosphorylation of NCC and elevated blood pressure were completely corrected, indicating that Phosphorylation of SPAK and OSR1 by WNK kinases is required for the increased activation and Phosphorylation of NCC in this model. Renal phosphorylated Akt was increased in db/db mice, suggesting that increased NCC Phosphorylation is regulated by the PI3K/Akt signaling Cascade in the kidney in response to hyperinsulinemia. A PI3K inhibitor (NVP-BEZ235) corrected the increased OSR1/SPAK-NCC Phosphorylation. Another more specific PI3K inhibitor (GDC-0941) and an Akt inhibitor (MK-2206) also inhibited increased NCC Phosphorylation. These results indicate that the PI3K/Akt signaling pathway activates the WNK-OSR1/SPAK-NCC Phosphorylation Cascade in db/db mice. This mechanism may play a role in the pathogenesis of salt-sensitive hypertension in human hyperinsulinemic conditions such as the metabolic syndrome.

  • phosphatidylinositol 3 kinase akt signaling pathway activates the wnk osr1 spak ncc Phosphorylation Cascade in hyperinsulinemic db db mice
    Hypertension, 2012
    Co-Authors: Hidenori Nishida, Motoko Chiga, Naohiro Nomura, Eisei Sohara, Dario R. Alessi, Tatemitsu Rai, Sei Sasaki, Shinichi Uchida
    Abstract:

    Metabolic syndrome patients have insulin resistance, which causes hyperinsulinemia, which in turn causes aberrant increased renal sodium reabsorption. The precise mechanisms underlying this greater salt sensitivity of hyperinsulinemic patients remain unclear. Abnormal activation of the recently identified with-no-lysine kinase (WNK)-oxidative stress-responsive kinase 1 (OSR1)/STE20/SPS1-related proline/alanine-rich kinase (SPAK)-NaCl cotransporter (NCC) Phosphorylation Cascade results in the salt-sensitive hypertension of pseudohypoaldosteronism type II. Here, we report a study of renal WNK-OSR1/SPAK-NCC Cascade activation in the db/db mouse model of hyperinsulinemic metabolic syndrome. Thiazide sensitivity was increased, suggesting greater activity of NCC in db/db mice. In fact, increased Phosphorylation of OSR1/SPAK and NCC was observed. In both SpakT243A/+ and Osr1T185A/+ knock-in db/db mice, which carry mutations that disrupt the signal from WNK kinases, increased Phosphorylation of NCC and elevated blood pressure were completely corrected, indicating that Phosphorylation of SPAK and OSR1 by WNK kinases is required for the increased activation and Phosphorylation of NCC in this model. Renal phosphorylated Akt was increased in db/db mice, suggesting that increased NCC Phosphorylation is regulated by the phosphatidylinositol 3-kinase/Akt signaling Cascade in the kidney in response to hyperinsulinemia. A phosphatidylinositol 3-kinase inhibitor (NVP-BEZ235) corrected the increased OSR1/SPAK-NCC Phosphorylation. Another more specific phosphatidylinositol 3-kinase inhibitor (GDC-0941) and an Akt inhibitor (MK-2206) also inhibited increased NCC Phosphorylation. These results indicate that the phosphatidylinositol 3-kinase/Akt signaling pathway activates the WNK-OSR1/SPAK-NCC Phosphorylation Cascade in db/db mice. This mechanism may play a role in the pathogenesis of salt-sensitive hypertension in human hyperinsulinemic conditions, such as the metabolic syndrome.

Sei Sasaki - One of the best experts on this subject based on the ideXlab platform.

  • pi3k akt signaling pathway activates the wnk osr1 spak ncc Phosphorylation Cascade in hyperinsulinemic db db mice
    Hypertension, 2012
    Co-Authors: Hidenori Nishida, Motoko Chiga, Naohiro Nomura, Eisei Sohara, Dario R. Alessi, Tatemitsu Rai, Sei Sasaki, Shinichi Uchida
    Abstract:

    Metabolic syndrome patients have insulin resistance, which causes hyperinsulinemia, which in turn causes aberrant increased renal sodium reabsorption. The precise mechanisms underlying this greater salt-sensitivity of hyperinsulinemic patients remain unclear. Abnormal activation of the recently-identified WNK kinase-OSR1/SPAK kinases-NCC transporter Phosphorylation Cascade results in the salt-sensitive hypertension of pseudohypoaldosteronism type II. Here, we report a study of renal WNK-OSR1/SPAK-NCC Cascade activation in the db/db mouse model of hyperinsulinemic metabolic syndrome. Thiazide sensitivity was increased, suggesting greater activity of NCC in db/db mice. In fact, increased Phosphorylation of OSR1/SPAK and NCC was observed. In both SpakT243A/+ and Osr1T185A/+ knock-in db/db mice, which carry mutations that disrupt the signal from WNK kinases, increased Phosphorylation of NCC and elevated blood pressure were completely corrected, indicating that Phosphorylation of SPAK and OSR1 by WNK kinases is required for the increased activation and Phosphorylation of NCC in this model. Renal phosphorylated Akt was increased in db/db mice, suggesting that increased NCC Phosphorylation is regulated by the PI3K/Akt signaling Cascade in the kidney in response to hyperinsulinemia. A PI3K inhibitor (NVP-BEZ235) corrected the increased OSR1/SPAK-NCC Phosphorylation. Another more specific PI3K inhibitor (GDC-0941) and an Akt inhibitor (MK-2206) also inhibited increased NCC Phosphorylation. These results indicate that the PI3K/Akt signaling pathway activates the WNK-OSR1/SPAK-NCC Phosphorylation Cascade in db/db mice. This mechanism may play a role in the pathogenesis of salt-sensitive hypertension in human hyperinsulinemic conditions such as the metabolic syndrome.

  • phosphatidylinositol 3 kinase akt signaling pathway activates the wnk osr1 spak ncc Phosphorylation Cascade in hyperinsulinemic db db micenovelty and significance
    Hypertension, 2012
    Co-Authors: Hidenori Nishida, Motoko Chiga, Naohiro Nomura, Eisei Sohara, Dario R. Alessi, Tatemitsu Rai, Sei Sasaki, Shinichi Uchida
    Abstract:

    Metabolic syndrome patients have insulin resistance, which causes hyperinsulinemia, which in turn causes aberrant increased renal sodium reabsorption. The precise mechanisms underlying this greater salt sensitivity of hyperinsulinemic patients remain unclear. Abnormal activation of the recently identified with-no-lysine kinase (WNK)-oxidative stress-responsive kinase 1 (OSR1)/STE20/SPS1-related proline/alanine-rich kinase (SPAK)-NaCl cotransporter (NCC) Phosphorylation Cascade results in the salt-sensitive hypertension of pseudohypoaldosteronism type II. Here, we report a study of renal WNK-OSR1/SPAK-NCC Cascade activation in the db/db mouse model of hyperinsulinemic metabolic syndrome. Thiazide sensitivity was increased, suggesting greater activity of NCC in db/db mice. In fact, increased Phosphorylation of OSR1/SPAK and NCC was observed. In both Spak T243A/+ and Osr1 T185A/+ knock-in db/db mice, which carry mutations that disrupt the signal from WNK kinases, increased Phosphorylation of NCC and elevated blood pressure were completely corrected, indicating that Phosphorylation of SPAK and OSR1 by WNK kinases is required for the increased activation and Phosphorylation of NCC in this model. Renal phosphorylated Akt was increased in db/db mice, suggesting that increased NCC Phosphorylation is regulated by the phosphatidylinositol 3-kinase/Akt signaling Cascade in the kidney in response to hyperinsulinemia. A phosphatidylinositol 3-kinase inhibitor (NVP-BEZ235) corrected the increased OSR1/SPAK-NCC Phosphorylation. Another more specific phosphatidylinositol 3-kinase inhibitor (GDC-0941) and an Akt inhibitor (MK-2206) also inhibited increased NCC Phosphorylation. These results indicate that the phosphatidylinositol 3-kinase/Akt signaling pathway activates the WNK-OSR1/SPAK-NCC Phosphorylation Cascade in db/db mice. This mechanism may play a role in the pathogenesis of salt-sensitive hypertension in human hyperinsulinemic conditions, such as the metabolic syndrome.

  • PI3K/Akt Signaling Pathway Activates the WNK-OSR1/SPAK-NCC Phosphorylation Cascade in Hyperinsulinemic db/db Mice
    Hypertension (Dallas Tex. : 1979), 2012
    Co-Authors: Hidenori Nishida, Motoko Chiga, Naohiro Nomura, Eisei Sohara, Dario R. Alessi, Tatemitsu Rai, Sei Sasaki, Shinichi Uchida
    Abstract:

    Metabolic syndrome patients have insulin resistance, which causes hyperinsulinemia, which in turn causes aberrant increased renal sodium reabsorption. The precise mechanisms underlying this greater salt-sensitivity of hyperinsulinemic patients remain unclear. Abnormal activation of the recently-identified WNK kinase-OSR1/SPAK kinases-NCC transporter Phosphorylation Cascade results in the salt-sensitive hypertension of pseudohypoaldosteronism type II. Here, we report a study of renal WNK-OSR1/SPAK-NCC Cascade activation in the db/db mouse model of hyperinsulinemic metabolic syndrome. Thiazide sensitivity was increased, suggesting greater activity of NCC in db/db mice. In fact, increased Phosphorylation of OSR1/SPAK and NCC was observed. In both SpakT243A/+ and Osr1T185A/+ knock-in db/db mice, which carry mutations that disrupt the signal from WNK kinases, increased Phosphorylation of NCC and elevated blood pressure were completely corrected, indicating that Phosphorylation of SPAK and OSR1 by WNK kinases is required for the increased activation and Phosphorylation of NCC in this model. Renal phosphorylated Akt was increased in db/db mice, suggesting that increased NCC Phosphorylation is regulated by the PI3K/Akt signaling Cascade in the kidney in response to hyperinsulinemia. A PI3K inhibitor (NVP-BEZ235) corrected the increased OSR1/SPAK-NCC Phosphorylation. Another more specific PI3K inhibitor (GDC-0941) and an Akt inhibitor (MK-2206) also inhibited increased NCC Phosphorylation. These results indicate that the PI3K/Akt signaling pathway activates the WNK-OSR1/SPAK-NCC Phosphorylation Cascade in db/db mice. This mechanism may play a role in the pathogenesis of salt-sensitive hypertension in human hyperinsulinemic conditions such as the metabolic syndrome.

  • phosphatidylinositol 3 kinase akt signaling pathway activates the wnk osr1 spak ncc Phosphorylation Cascade in hyperinsulinemic db db mice
    Hypertension, 2012
    Co-Authors: Hidenori Nishida, Motoko Chiga, Naohiro Nomura, Eisei Sohara, Dario R. Alessi, Tatemitsu Rai, Sei Sasaki, Shinichi Uchida
    Abstract:

    Metabolic syndrome patients have insulin resistance, which causes hyperinsulinemia, which in turn causes aberrant increased renal sodium reabsorption. The precise mechanisms underlying this greater salt sensitivity of hyperinsulinemic patients remain unclear. Abnormal activation of the recently identified with-no-lysine kinase (WNK)-oxidative stress-responsive kinase 1 (OSR1)/STE20/SPS1-related proline/alanine-rich kinase (SPAK)-NaCl cotransporter (NCC) Phosphorylation Cascade results in the salt-sensitive hypertension of pseudohypoaldosteronism type II. Here, we report a study of renal WNK-OSR1/SPAK-NCC Cascade activation in the db/db mouse model of hyperinsulinemic metabolic syndrome. Thiazide sensitivity was increased, suggesting greater activity of NCC in db/db mice. In fact, increased Phosphorylation of OSR1/SPAK and NCC was observed. In both SpakT243A/+ and Osr1T185A/+ knock-in db/db mice, which carry mutations that disrupt the signal from WNK kinases, increased Phosphorylation of NCC and elevated blood pressure were completely corrected, indicating that Phosphorylation of SPAK and OSR1 by WNK kinases is required for the increased activation and Phosphorylation of NCC in this model. Renal phosphorylated Akt was increased in db/db mice, suggesting that increased NCC Phosphorylation is regulated by the phosphatidylinositol 3-kinase/Akt signaling Cascade in the kidney in response to hyperinsulinemia. A phosphatidylinositol 3-kinase inhibitor (NVP-BEZ235) corrected the increased OSR1/SPAK-NCC Phosphorylation. Another more specific phosphatidylinositol 3-kinase inhibitor (GDC-0941) and an Akt inhibitor (MK-2206) also inhibited increased NCC Phosphorylation. These results indicate that the phosphatidylinositol 3-kinase/Akt signaling pathway activates the WNK-OSR1/SPAK-NCC Phosphorylation Cascade in db/db mice. This mechanism may play a role in the pathogenesis of salt-sensitive hypertension in human hyperinsulinemic conditions, such as the metabolic syndrome.

  • effect of angiotensin ii on the wnk osr1 spak ncc Phosphorylation Cascade in cultured mpkdct cells and in vivo mouse kidney
    Biochemical and Biophysical Research Communications, 2010
    Co-Authors: Gulibaha Talati, Eisei Sohara, Tatemitsu Rai, Sei Sasaki, Akihito Ohta, Shotaro Naito, Alain Vandewalle, Shinichi Uchida
    Abstract:

    In our recent study using Wnk4(D561A/+) knockin mice, we determined that the WNK-OSR1/SPAK-NaCl cotransporter (NCC) Phosphorylation Cascade is important for regulating NCC function in vivo. Phosphorylation of NCC was necessary for its plasma membrane localization. Previously, angiotensin II infusion was shown to increase apical membrane expression of NCC in rats. Therefore, we investigated whether angiotensin II was an upstream regulator for the WNK-OSR1/SPAK-NCC Cascade in cultured cells and in vivo kidney. In mpkDCT cells, the Phosphorylation of OSR1 and NCC was increased 30 min after the addition of angiotensin II (10(-9)-10(-7)M) but returned to baseline after 18 h. In mice, a 5-min infusion of angiotensin II (5 ng/g/min) increased NCC Phosphorylation in the kidney at 30 min and 2h after the injection but returned to baseline 24h later. This increase was inhibited by angiotensin II receptor blocker (valsartan) but not by aldosterone receptor blocker (eplerenone). Ten-day infusions of angiotensin II (720 ng/day) also increased Phosphorylation of OSR1 and NCC in the mouse kidney, and both valsartan and eplerenone inhibited the increased Phosphorylation. Although angiotensin II is identified as an upstream regulator for the WNK-OSR1/SPAK-NCC Cascade in vivo, aldosterone appears to be the major regulator of this signal Cascade in the long-term regulation by angiotensin II.

Motoko Chiga - One of the best experts on this subject based on the ideXlab platform.

  • Evaluation of Phosphorylated Urinary Na-Cl Cotransporter Is Potentially Useful in a Patient With Pseudohypoaldosteronism Type II due to Mutation in CUL3.
    Global Pediatric Health, 2014
    Co-Authors: Keiko Nagahara, Motoko Chiga, Kiyoshi Isobe, Shinichi Uchida, Yoshifusa Abe, Akira Hojo, Kazushige Dobashi, Kazuo Itabashi
    Abstract:

    Pseudohypoaldosteronism type II (PHA II), which is also known as Gordon syndrome, is a rare autosomal dominant disease characterized by hypertension, hyperkalemia, hyperchloremic metabolic acidosis, and the absence of hyponatremia and hyperaldosteronemia.1 The pathophysiology of PHA II is explained by the constitutive activation of WNK (with no lysine) kinases–OSR1/SPAK kinases–sodium/chloride cotransporter (NCC) Phosphorylation Cascade. NCC is distributed on the apical plasma membranes of the distal convoluted tubules, and activation of NCC mediates increasing sodium chloride (NaCl) reabsorption in the kidney, leading to hypertension, hyperkalemia, and metabolic acidosis.2 Mutations of 4 genes, WNK1, WNK4, KLHL3 (Kelch-like 3), and CUL3 (Cullin 3), have been reported to be responsible to PHA II.3,4 Here, we present the case of a 6-year-old Japanese boy with PHA II. Our case is the third one with novel mutation in CUL3 gene. We also studied the excretion of urinary total NCC (tNCC) and phosphorylated NCC (pNCC) in his family members.

  • impaired degradation of wnk1 and wnk4 kinases causes phaii in mutant klhl3 knock in mice
    Human Molecular Genetics, 2014
    Co-Authors: Koichiro Susa, Moko Zeniya, Hidenori Nishida, Daiei Takahashi, Motoko Chiga, Naohiro Nomura, Yutaro Mori, Takayasu Mori, Eisei Sohara, Kiyoshi Isobe
    Abstract:

    Pseudohypoaldosteronism type II (PHAII) is a hereditary disease characterized by salt-sensitive hypertension, hyperkalemia and metabolic acidosis, and genes encoding with-no-lysine kinase 1 (WNK1) and WNK4 kinases are known to be responsible. Recently, Kelch-like 3 (KLHL3) and Cullin3, components of KLHL3-Cullin3 E3 ligase, were newly identified as responsible for PHAII. We have reported that WNK4 is the substrate of KLHL3Cullin3 E3 ligase-mediated ubiquitination. However, WNK1 and Na‐Cl cotransporter (NCC) were also reported tobeasubstrateofKLHL3-Cullin3E3ligasebyothergroups.Therefore,itremainsunclearwhichmoleculeisthe target(s)ofKLHL3.ToinvestigatethepathogenesisofPHAIIcausedbyKLHL3mutation,wegeneratedandanalyzedKLHL3 R528H/1 knock-inmice.KLHL3 R528H/1 knock-inmiceexhibitedsalt-sensitivehypertension,hyperkalemiaandmetabolicacidosis.Moreover,thePhosphorylationofNCCwasincreasedintheKLHL3 R528H/1 mouse kidney,indicatingthattheKLHL3 R528H/1 knock-inmouseisanidealmousemodelofPHAII.Interestingly,theprotein expression of both WNK1 and WNK4 was significantly increased in the KLHL3 R528H/1 mouse kidney, confirming that increases in these WNK kinases activated the WNK-OSR1/SPAK-NCC Phosphorylation Cascade in KLHL3 R528H/1 knock-in mice. To examine whether mutant KLHL3 R528H can interact with WNK kinases, we measuredthebindingofTAMRA-labeledWNK1andWNK4peptidestofull-lengthKLHL3usingfluorescencecor

  • dietary salt intake regulates wnk3 spak nkcc1 Phosphorylation Cascade in mouse aorta through angiotensin ii
    Hypertension, 2013
    Co-Authors: Moko Zeniya, Daiei Takahashi, Koichiro Susa, Motoko Chiga, Takayasu Mori, Eisei Sohara, Satomi Kita, Takahiro Iwamoto, Sung-sen Yang, Shihhua Lin
    Abstract:

    Na-K-Cl cotransporter isoform 1 (NKCC1) is involved in the regulation of vascular smooth muscle cell contraction. Recently, the with-no-lysine kinase (WNK)-STE20/SPS1-related proline/alanine-rich kinase (SPAK)-NKCC1 Phosphorylation Cascade in vascular smooth muscle cells was found to be important in the regulation of vascular tone. In this study, we investigated whether the WNK-SPAK-NKCC1 Cascade in mouse aortic tissue is regulated by dietary salt intake and the mechanisms responsible. Phosphorylation of SPAK and NKCC1 was significantly reduced in the aorta in high-salt-fed mice and was increased in the aorta in low-salt-fed mice, indicating that the WNK-SPAK-NKCC1 Phosphorylation Cascade in the aorta was indeed regulated by dietary salt intake. Acute and chronic angiotensin II infusion increased Phosphorylation of SPAK and NKCC1 in the mouse aorta. In addition, valsartan, an antagonist of angiotensin II type 1 receptor, inhibited low-salt diet-induced Phosphorylation of SPAK and NKCC1, demonstrating that angiotensin II activates the WNK-SPAK-NKCC1 Phosphorylation Cascade through the angiotensin II type 1 receptor. However, a low-salt diet and angiotensin II together did not increase Phosphorylation of SPAK and NKCC1 in the aorta in WNK3 knockout mice, indicating that activation of the WNK-SPAK-NKCC1 Phosphorylation Cascade induced by a low-salt diet and angiotensin II is dependent on WNK3. Indeed, angiotensin II-induced increases in blood pressure were diminished in WNK3 knockout mice. In addition, decreased response to angiotensin II in the mesenteric arteries was observed in WNK3 knockout mice. Our data also clarified a novel mechanism for regulation of vascular tonus by angiotensin II. Inhibition of this Cascade could, therefore, be a novel therapeutic target in hypertension.

  • Dietary Salt Intake Regulates WNK3–SPAK–NKCC1 Phosphorylation Cascade in Mouse Aorta Through Angiotensin II
    Hypertension (Dallas Tex. : 1979), 2013
    Co-Authors: Moko Zeniya, Daiei Takahashi, Koichiro Susa, Motoko Chiga, Takayasu Mori, Eisei Sohara, Satomi Kita, Takahiro Iwamoto, Sung-sen Yang
    Abstract:

    Na-K-Cl cotransporter isoform 1 (NKCC1) is involved in the regulation of vascular smooth muscle cell contraction. Recently, the with-no-lysine kinase (WNK)-STE20/SPS1-related proline/alanine-rich kinase (SPAK)-NKCC1 Phosphorylation Cascade in vascular smooth muscle cells was found to be important in the regulation of vascular tone. In this study, we investigated whether the WNK-SPAK-NKCC1 Cascade in mouse aortic tissue is regulated by dietary salt intake and the mechanisms responsible. Phosphorylation of SPAK and NKCC1 was significantly reduced in the aorta in high-salt-fed mice and was increased in the aorta in low-salt-fed mice, indicating that the WNK-SPAK-NKCC1 Phosphorylation Cascade in the aorta was indeed regulated by dietary salt intake. Acute and chronic angiotensin II infusion increased Phosphorylation of SPAK and NKCC1 in the mouse aorta. In addition, valsartan, an antagonist of angiotensin II type 1 receptor, inhibited low-salt diet-induced Phosphorylation of SPAK and NKCC1, demonstrating that angiotensin II activates the WNK-SPAK-NKCC1 Phosphorylation Cascade through the angiotensin II type 1 receptor. However, a low-salt diet and angiotensin II together did not increase Phosphorylation of SPAK and NKCC1 in the aorta in WNK3 knockout mice, indicating that activation of the WNK-SPAK-NKCC1 Phosphorylation Cascade induced by a low-salt diet and angiotensin II is dependent on WNK3. Indeed, angiotensin II-induced increases in blood pressure were diminished in WNK3 knockout mice. In addition, decreased response to angiotensin II in the mesenteric arteries was observed in WNK3 knockout mice. Our data also clarified a novel mechanism for regulation of vascular tonus by angiotensin II. Inhibition of this Cascade could, therefore, be a novel therapeutic target in hypertension.

  • pi3k akt signaling pathway activates the wnk osr1 spak ncc Phosphorylation Cascade in hyperinsulinemic db db mice
    Hypertension, 2012
    Co-Authors: Hidenori Nishida, Motoko Chiga, Naohiro Nomura, Eisei Sohara, Dario R. Alessi, Tatemitsu Rai, Sei Sasaki, Shinichi Uchida
    Abstract:

    Metabolic syndrome patients have insulin resistance, which causes hyperinsulinemia, which in turn causes aberrant increased renal sodium reabsorption. The precise mechanisms underlying this greater salt-sensitivity of hyperinsulinemic patients remain unclear. Abnormal activation of the recently-identified WNK kinase-OSR1/SPAK kinases-NCC transporter Phosphorylation Cascade results in the salt-sensitive hypertension of pseudohypoaldosteronism type II. Here, we report a study of renal WNK-OSR1/SPAK-NCC Cascade activation in the db/db mouse model of hyperinsulinemic metabolic syndrome. Thiazide sensitivity was increased, suggesting greater activity of NCC in db/db mice. In fact, increased Phosphorylation of OSR1/SPAK and NCC was observed. In both SpakT243A/+ and Osr1T185A/+ knock-in db/db mice, which carry mutations that disrupt the signal from WNK kinases, increased Phosphorylation of NCC and elevated blood pressure were completely corrected, indicating that Phosphorylation of SPAK and OSR1 by WNK kinases is required for the increased activation and Phosphorylation of NCC in this model. Renal phosphorylated Akt was increased in db/db mice, suggesting that increased NCC Phosphorylation is regulated by the PI3K/Akt signaling Cascade in the kidney in response to hyperinsulinemia. A PI3K inhibitor (NVP-BEZ235) corrected the increased OSR1/SPAK-NCC Phosphorylation. Another more specific PI3K inhibitor (GDC-0941) and an Akt inhibitor (MK-2206) also inhibited increased NCC Phosphorylation. These results indicate that the PI3K/Akt signaling pathway activates the WNK-OSR1/SPAK-NCC Phosphorylation Cascade in db/db mice. This mechanism may play a role in the pathogenesis of salt-sensitive hypertension in human hyperinsulinemic conditions such as the metabolic syndrome.

Tatemitsu Rai - One of the best experts on this subject based on the ideXlab platform.

  • pi3k akt signaling pathway activates the wnk osr1 spak ncc Phosphorylation Cascade in hyperinsulinemic db db mice
    Hypertension, 2012
    Co-Authors: Hidenori Nishida, Motoko Chiga, Naohiro Nomura, Eisei Sohara, Dario R. Alessi, Tatemitsu Rai, Sei Sasaki, Shinichi Uchida
    Abstract:

    Metabolic syndrome patients have insulin resistance, which causes hyperinsulinemia, which in turn causes aberrant increased renal sodium reabsorption. The precise mechanisms underlying this greater salt-sensitivity of hyperinsulinemic patients remain unclear. Abnormal activation of the recently-identified WNK kinase-OSR1/SPAK kinases-NCC transporter Phosphorylation Cascade results in the salt-sensitive hypertension of pseudohypoaldosteronism type II. Here, we report a study of renal WNK-OSR1/SPAK-NCC Cascade activation in the db/db mouse model of hyperinsulinemic metabolic syndrome. Thiazide sensitivity was increased, suggesting greater activity of NCC in db/db mice. In fact, increased Phosphorylation of OSR1/SPAK and NCC was observed. In both SpakT243A/+ and Osr1T185A/+ knock-in db/db mice, which carry mutations that disrupt the signal from WNK kinases, increased Phosphorylation of NCC and elevated blood pressure were completely corrected, indicating that Phosphorylation of SPAK and OSR1 by WNK kinases is required for the increased activation and Phosphorylation of NCC in this model. Renal phosphorylated Akt was increased in db/db mice, suggesting that increased NCC Phosphorylation is regulated by the PI3K/Akt signaling Cascade in the kidney in response to hyperinsulinemia. A PI3K inhibitor (NVP-BEZ235) corrected the increased OSR1/SPAK-NCC Phosphorylation. Another more specific PI3K inhibitor (GDC-0941) and an Akt inhibitor (MK-2206) also inhibited increased NCC Phosphorylation. These results indicate that the PI3K/Akt signaling pathway activates the WNK-OSR1/SPAK-NCC Phosphorylation Cascade in db/db mice. This mechanism may play a role in the pathogenesis of salt-sensitive hypertension in human hyperinsulinemic conditions such as the metabolic syndrome.

  • phosphatidylinositol 3 kinase akt signaling pathway activates the wnk osr1 spak ncc Phosphorylation Cascade in hyperinsulinemic db db micenovelty and significance
    Hypertension, 2012
    Co-Authors: Hidenori Nishida, Motoko Chiga, Naohiro Nomura, Eisei Sohara, Dario R. Alessi, Tatemitsu Rai, Sei Sasaki, Shinichi Uchida
    Abstract:

    Metabolic syndrome patients have insulin resistance, which causes hyperinsulinemia, which in turn causes aberrant increased renal sodium reabsorption. The precise mechanisms underlying this greater salt sensitivity of hyperinsulinemic patients remain unclear. Abnormal activation of the recently identified with-no-lysine kinase (WNK)-oxidative stress-responsive kinase 1 (OSR1)/STE20/SPS1-related proline/alanine-rich kinase (SPAK)-NaCl cotransporter (NCC) Phosphorylation Cascade results in the salt-sensitive hypertension of pseudohypoaldosteronism type II. Here, we report a study of renal WNK-OSR1/SPAK-NCC Cascade activation in the db/db mouse model of hyperinsulinemic metabolic syndrome. Thiazide sensitivity was increased, suggesting greater activity of NCC in db/db mice. In fact, increased Phosphorylation of OSR1/SPAK and NCC was observed. In both Spak T243A/+ and Osr1 T185A/+ knock-in db/db mice, which carry mutations that disrupt the signal from WNK kinases, increased Phosphorylation of NCC and elevated blood pressure were completely corrected, indicating that Phosphorylation of SPAK and OSR1 by WNK kinases is required for the increased activation and Phosphorylation of NCC in this model. Renal phosphorylated Akt was increased in db/db mice, suggesting that increased NCC Phosphorylation is regulated by the phosphatidylinositol 3-kinase/Akt signaling Cascade in the kidney in response to hyperinsulinemia. A phosphatidylinositol 3-kinase inhibitor (NVP-BEZ235) corrected the increased OSR1/SPAK-NCC Phosphorylation. Another more specific phosphatidylinositol 3-kinase inhibitor (GDC-0941) and an Akt inhibitor (MK-2206) also inhibited increased NCC Phosphorylation. These results indicate that the phosphatidylinositol 3-kinase/Akt signaling pathway activates the WNK-OSR1/SPAK-NCC Phosphorylation Cascade in db/db mice. This mechanism may play a role in the pathogenesis of salt-sensitive hypertension in human hyperinsulinemic conditions, such as the metabolic syndrome.

  • PI3K/Akt Signaling Pathway Activates the WNK-OSR1/SPAK-NCC Phosphorylation Cascade in Hyperinsulinemic db/db Mice
    Hypertension (Dallas Tex. : 1979), 2012
    Co-Authors: Hidenori Nishida, Motoko Chiga, Naohiro Nomura, Eisei Sohara, Dario R. Alessi, Tatemitsu Rai, Sei Sasaki, Shinichi Uchida
    Abstract:

    Metabolic syndrome patients have insulin resistance, which causes hyperinsulinemia, which in turn causes aberrant increased renal sodium reabsorption. The precise mechanisms underlying this greater salt-sensitivity of hyperinsulinemic patients remain unclear. Abnormal activation of the recently-identified WNK kinase-OSR1/SPAK kinases-NCC transporter Phosphorylation Cascade results in the salt-sensitive hypertension of pseudohypoaldosteronism type II. Here, we report a study of renal WNK-OSR1/SPAK-NCC Cascade activation in the db/db mouse model of hyperinsulinemic metabolic syndrome. Thiazide sensitivity was increased, suggesting greater activity of NCC in db/db mice. In fact, increased Phosphorylation of OSR1/SPAK and NCC was observed. In both SpakT243A/+ and Osr1T185A/+ knock-in db/db mice, which carry mutations that disrupt the signal from WNK kinases, increased Phosphorylation of NCC and elevated blood pressure were completely corrected, indicating that Phosphorylation of SPAK and OSR1 by WNK kinases is required for the increased activation and Phosphorylation of NCC in this model. Renal phosphorylated Akt was increased in db/db mice, suggesting that increased NCC Phosphorylation is regulated by the PI3K/Akt signaling Cascade in the kidney in response to hyperinsulinemia. A PI3K inhibitor (NVP-BEZ235) corrected the increased OSR1/SPAK-NCC Phosphorylation. Another more specific PI3K inhibitor (GDC-0941) and an Akt inhibitor (MK-2206) also inhibited increased NCC Phosphorylation. These results indicate that the PI3K/Akt signaling pathway activates the WNK-OSR1/SPAK-NCC Phosphorylation Cascade in db/db mice. This mechanism may play a role in the pathogenesis of salt-sensitive hypertension in human hyperinsulinemic conditions such as the metabolic syndrome.

  • phosphatidylinositol 3 kinase akt signaling pathway activates the wnk osr1 spak ncc Phosphorylation Cascade in hyperinsulinemic db db mice
    Hypertension, 2012
    Co-Authors: Hidenori Nishida, Motoko Chiga, Naohiro Nomura, Eisei Sohara, Dario R. Alessi, Tatemitsu Rai, Sei Sasaki, Shinichi Uchida
    Abstract:

    Metabolic syndrome patients have insulin resistance, which causes hyperinsulinemia, which in turn causes aberrant increased renal sodium reabsorption. The precise mechanisms underlying this greater salt sensitivity of hyperinsulinemic patients remain unclear. Abnormal activation of the recently identified with-no-lysine kinase (WNK)-oxidative stress-responsive kinase 1 (OSR1)/STE20/SPS1-related proline/alanine-rich kinase (SPAK)-NaCl cotransporter (NCC) Phosphorylation Cascade results in the salt-sensitive hypertension of pseudohypoaldosteronism type II. Here, we report a study of renal WNK-OSR1/SPAK-NCC Cascade activation in the db/db mouse model of hyperinsulinemic metabolic syndrome. Thiazide sensitivity was increased, suggesting greater activity of NCC in db/db mice. In fact, increased Phosphorylation of OSR1/SPAK and NCC was observed. In both SpakT243A/+ and Osr1T185A/+ knock-in db/db mice, which carry mutations that disrupt the signal from WNK kinases, increased Phosphorylation of NCC and elevated blood pressure were completely corrected, indicating that Phosphorylation of SPAK and OSR1 by WNK kinases is required for the increased activation and Phosphorylation of NCC in this model. Renal phosphorylated Akt was increased in db/db mice, suggesting that increased NCC Phosphorylation is regulated by the phosphatidylinositol 3-kinase/Akt signaling Cascade in the kidney in response to hyperinsulinemia. A phosphatidylinositol 3-kinase inhibitor (NVP-BEZ235) corrected the increased OSR1/SPAK-NCC Phosphorylation. Another more specific phosphatidylinositol 3-kinase inhibitor (GDC-0941) and an Akt inhibitor (MK-2206) also inhibited increased NCC Phosphorylation. These results indicate that the phosphatidylinositol 3-kinase/Akt signaling pathway activates the WNK-OSR1/SPAK-NCC Phosphorylation Cascade in db/db mice. This mechanism may play a role in the pathogenesis of salt-sensitive hypertension in human hyperinsulinemic conditions, such as the metabolic syndrome.

  • effect of angiotensin ii on the wnk osr1 spak ncc Phosphorylation Cascade in cultured mpkdct cells and in vivo mouse kidney
    Biochemical and Biophysical Research Communications, 2010
    Co-Authors: Gulibaha Talati, Eisei Sohara, Tatemitsu Rai, Sei Sasaki, Akihito Ohta, Shotaro Naito, Alain Vandewalle, Shinichi Uchida
    Abstract:

    In our recent study using Wnk4(D561A/+) knockin mice, we determined that the WNK-OSR1/SPAK-NaCl cotransporter (NCC) Phosphorylation Cascade is important for regulating NCC function in vivo. Phosphorylation of NCC was necessary for its plasma membrane localization. Previously, angiotensin II infusion was shown to increase apical membrane expression of NCC in rats. Therefore, we investigated whether angiotensin II was an upstream regulator for the WNK-OSR1/SPAK-NCC Cascade in cultured cells and in vivo kidney. In mpkDCT cells, the Phosphorylation of OSR1 and NCC was increased 30 min after the addition of angiotensin II (10(-9)-10(-7)M) but returned to baseline after 18 h. In mice, a 5-min infusion of angiotensin II (5 ng/g/min) increased NCC Phosphorylation in the kidney at 30 min and 2h after the injection but returned to baseline 24h later. This increase was inhibited by angiotensin II receptor blocker (valsartan) but not by aldosterone receptor blocker (eplerenone). Ten-day infusions of angiotensin II (720 ng/day) also increased Phosphorylation of OSR1 and NCC in the mouse kidney, and both valsartan and eplerenone inhibited the increased Phosphorylation. Although angiotensin II is identified as an upstream regulator for the WNK-OSR1/SPAK-NCC Cascade in vivo, aldosterone appears to be the major regulator of this signal Cascade in the long-term regulation by angiotensin II.