The Experts below are selected from a list of 1527 Experts worldwide ranked by ideXlab platform
Manoocher Soleimani - One of the best experts on this subject based on the ideXlab platform.
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Probenecid Pre-treatment Downregulates the Kidney Cl-/HCO3- Exchanger (Pendrin) and Potentiates Hydrochlorothiazide-Induced Diuresis
Frontiers Media S.A., 2018Co-Authors: Manoocher Soleimani, Sharon Barone, Kamyar Zahedi, Marybeth BrooksAbstract:Background: Probenecid is a uricosuric agent that in addition to exerting a positive ionotropic effect in the heart, blocks the ATP transporter Pannexin 1 and inhibits the Cl-/HCO3- exchanger, Pendrin. In the kidney, Pendrin blunts the loss of salt wasting secondary to the inhibition of the thiazide-sensitive Na+-Cl- co-transporter (NCC/SLC12A3).Hypothesis: Pre-treatment with probenecid down-regulates Pendrin; therefore, leaving NCC as the main salt absorbing transporter in the distal nephron, and hence enhances the hydrochlorothiazide (HCTZ)-induced diuresis.Methods: Daily balance studies, blood and urine chemical analysis, immunofluorescence, as well as western and northern blot analyses were utilized to examine the effects of probenecid alone (at 250 mg/kg/day) or in combination with HCTZ (at 40 mg/kg/day) on kidney function and on salt and water transporters in the collecting duct.Results: Male Sprague Dawley rats were subjected to three different protocols: (1) HCTZ for 4 days, (2) probenecid for 10 days, and (3) primed with probenecid for 6 days followed by probenecid and HCTZ for 4 additional days. Treatment protocol 1 (HCTZ for 4 days) only mildly increased the urine volume (U Vol) from a baseline of 9.8–13.4 ml/day. In response to treatment protocol 2 (probenecid for 10 days), U Vol increased to 15.9 ml/24 h. Treatment protocol 3 (probenecid for 6 days followed by probenecid and HCTZ for 4 additional days) increased the U Vol to 42.9 ml/day on day 4 of co-treatment with HCTZ and probenecid (compared to probenecid p = 0.003, n = 5 or HCTZ alone p = 0.001, n = 5). Probenecid treatment at 250 mg/kg/day downregulated the expression of Pendrin and led to a decrease in AQP2 expression. Enhanced diuresis by probenecid plus HCTZ was not associated with volume depletion.Conclusion: Probenecid pre-treatment downregulates Pendrin and robustly enhances diuresis by HCTZ-mediated NCC inhibition in kidney
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Echocardiography in anesthetized WT and Pendrin/NCC dKO mice before and after HCTZ.
2017Co-Authors: Saeed Alshahrani, Sharon Barone, Kamyar Zahedi, Robert M. Rapoport, Min Jiang, Michelle Nieman, Andrea L. Meredith, John N. Lorenz, Jack Rubinstein, Manoocher SoleimaniAbstract:(a) M-mode images of cardiac function of WT and Pendrin/NCC dKO mice before and after HCTZ. (b) The examination of cardiac index as measured by echocardiography does not demonstrate any significant reduction in cardiac output of Pendrin/NCC dKO mice after HCTZ treatment (n = 4 each group).
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Intravascular volume depletion in Pendrin/NCC dKO mice.
2017Co-Authors: Saeed Alshahrani, Sharon Barone, Kamyar Zahedi, Robert M. Rapoport, Min Jiang, Michelle Nieman, Andrea L. Meredith, John N. Lorenz, Jack Rubinstein, Manoocher SoleimaniAbstract:(a) Northern hybridization shows a significant enhancement in mRNA expression levels of renin in kidneys of Pendrin/NCC dKO mice compared to WT, Pendrin KO and NCC KO. (b) Immunofluorescent microscopic analysis of kidney sections indicates that the expression of renin is significantly up regulated in Pendrin/NCC dKO, but not in WT mice. (c) Western blots confirmed the significant increase in renin expression in Pendrin/NCC dKO kidney vs WT. (d) Olmesartan (1 mg/kg) treatment causes a more significant reduction in the systolic BP of Pendrin/NCC dKO mice compared to WT mice, (n = 4 each group); paired t-test * P
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Ablation of the Cl-/HCO3- Exchanger Pendrin Enhances Hydrochlorothiazide-Induced Diuresis
Karger Publishers, 2017Co-Authors: Saeed Alshahrani, Manoocher SoleimaniAbstract:Background/Aims: The Cl-/HCO3- exchanger Pendrin and the thiazide-sensitive Na-Cl cotransporter NCC are expressed in the kidney distal nephron and mediate salt absorption. We hypothesized that deletion of Pendrin leaves NCC as the major salt absorbing transporter in the distal nephron and therefore enhances salt excretion by hydrochlorothiazide (HCTZ). Methods: Metabolic cage studies were performed in wild type, Pendrin KO and NCC KO mice at baseline and following HCTZ treatment. In parallel studies, systemic blood pressure was measured in mice treated with HCTZ with the tail cuff method. Results: Urine output, salt excretion and water intake were comparable in all groups under baseline condition. Urine output and water intake increased significantly only in Pendrin KO mice in response to HCTZ, but not in WT or NCC KO mice. Sodium and chloride excretion increased in HCTZ-treated Pendrin KO mice, but they remained unchanged in WT or NCC KO mice. Pendrin KO mice treated with HCTZ developed volume depletion, as determined by increased expression of renin mRNA and protein. The expression of ENaC and Pendrin increased in HCTZ-treated WT mice. HCTZ treatment did not significantly modify blood pressure in any of the experimental group. Conclusion: The ablation of the Cl-/HCO3- exchanger Pendrin enhances the magnitude of salt wasting by HCTZ
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Effects of HCTZ on Pendrin/NCC dKO mice: Role of volume depletion.
2017Co-Authors: Saeed Alshahrani, Sharon Barone, Kamyar Zahedi, Robert M. Rapoport, Min Jiang, Michelle Nieman, Andrea L. Meredith, John N. Lorenz, Jack Rubinstein, Manoocher SoleimaniAbstract:(a) The systolic BP of Pendrin/NCC dKO mice dropped below detectable levels at 1 and 3 hours after HCTZ treatment but returned to baseline levels at 6 and 24 hours later; the systolic BP of WT mice was not significantly affected by HCTZ (#; below detectable level; n = 4). (b) Baseline (BL) blood pressure of Pendrin/NCC dKO mice and WT mice was measured on normal (1% NaCl) diet. Then, mice were placed on high salt (7% NaCl) diets for up to 14 days. On day 14, animals’ baseline (BL) blood pressure was measured and then treated with HCTZ, and their BP was measured at 1, 3, 6, and 24 hours (h). The effect of HCTZ is abrogated in euvolemic Pendrin/NCC dKO mice. (c) Treatment with a high salt diet reduces the renal expression of renin in Pendrin/NCC dKO mice, indicating the correction of the volume depletion (n = 3).
Sharon Barone - One of the best experts on this subject based on the ideXlab platform.
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Probenecid Pre-treatment Downregulates the Kidney Cl-/HCO3- Exchanger (Pendrin) and Potentiates Hydrochlorothiazide-Induced Diuresis
Frontiers Media S.A., 2018Co-Authors: Manoocher Soleimani, Sharon Barone, Kamyar Zahedi, Marybeth BrooksAbstract:Background: Probenecid is a uricosuric agent that in addition to exerting a positive ionotropic effect in the heart, blocks the ATP transporter Pannexin 1 and inhibits the Cl-/HCO3- exchanger, Pendrin. In the kidney, Pendrin blunts the loss of salt wasting secondary to the inhibition of the thiazide-sensitive Na+-Cl- co-transporter (NCC/SLC12A3).Hypothesis: Pre-treatment with probenecid down-regulates Pendrin; therefore, leaving NCC as the main salt absorbing transporter in the distal nephron, and hence enhances the hydrochlorothiazide (HCTZ)-induced diuresis.Methods: Daily balance studies, blood and urine chemical analysis, immunofluorescence, as well as western and northern blot analyses were utilized to examine the effects of probenecid alone (at 250 mg/kg/day) or in combination with HCTZ (at 40 mg/kg/day) on kidney function and on salt and water transporters in the collecting duct.Results: Male Sprague Dawley rats were subjected to three different protocols: (1) HCTZ for 4 days, (2) probenecid for 10 days, and (3) primed with probenecid for 6 days followed by probenecid and HCTZ for 4 additional days. Treatment protocol 1 (HCTZ for 4 days) only mildly increased the urine volume (U Vol) from a baseline of 9.8–13.4 ml/day. In response to treatment protocol 2 (probenecid for 10 days), U Vol increased to 15.9 ml/24 h. Treatment protocol 3 (probenecid for 6 days followed by probenecid and HCTZ for 4 additional days) increased the U Vol to 42.9 ml/day on day 4 of co-treatment with HCTZ and probenecid (compared to probenecid p = 0.003, n = 5 or HCTZ alone p = 0.001, n = 5). Probenecid treatment at 250 mg/kg/day downregulated the expression of Pendrin and led to a decrease in AQP2 expression. Enhanced diuresis by probenecid plus HCTZ was not associated with volume depletion.Conclusion: Probenecid pre-treatment downregulates Pendrin and robustly enhances diuresis by HCTZ-mediated NCC inhibition in kidney
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Effects of HCTZ on Pendrin/NCC dKO mice: Role of volume depletion.
2017Co-Authors: Saeed Alshahrani, Sharon Barone, Kamyar Zahedi, Robert M. Rapoport, Min Jiang, Michelle Nieman, Andrea L. Meredith, John N. Lorenz, Jack Rubinstein, Manoocher SoleimaniAbstract:(a) The systolic BP of Pendrin/NCC dKO mice dropped below detectable levels at 1 and 3 hours after HCTZ treatment but returned to baseline levels at 6 and 24 hours later; the systolic BP of WT mice was not significantly affected by HCTZ (#; below detectable level; n = 4). (b) Baseline (BL) blood pressure of Pendrin/NCC dKO mice and WT mice was measured on normal (1% NaCl) diet. Then, mice were placed on high salt (7% NaCl) diets for up to 14 days. On day 14, animals’ baseline (BL) blood pressure was measured and then treated with HCTZ, and their BP was measured at 1, 3, 6, and 24 hours (h). The effect of HCTZ is abrogated in euvolemic Pendrin/NCC dKO mice. (c) Treatment with a high salt diet reduces the renal expression of renin in Pendrin/NCC dKO mice, indicating the correction of the volume depletion (n = 3).
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Intravascular volume depletion in Pendrin/NCC dKO mice.
2017Co-Authors: Saeed Alshahrani, Sharon Barone, Kamyar Zahedi, Robert M. Rapoport, Min Jiang, Michelle Nieman, Andrea L. Meredith, John N. Lorenz, Jack Rubinstein, Manoocher SoleimaniAbstract:(a) Northern hybridization shows a significant enhancement in mRNA expression levels of renin in kidneys of Pendrin/NCC dKO mice compared to WT, Pendrin KO and NCC KO. (b) Immunofluorescent microscopic analysis of kidney sections indicates that the expression of renin is significantly up regulated in Pendrin/NCC dKO, but not in WT mice. (c) Western blots confirmed the significant increase in renin expression in Pendrin/NCC dKO kidney vs WT. (d) Olmesartan (1 mg/kg) treatment causes a more significant reduction in the systolic BP of Pendrin/NCC dKO mice compared to WT mice, (n = 4 each group); paired t-test * P
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Echocardiography in anesthetized WT and Pendrin/NCC dKO mice before and after HCTZ.
2017Co-Authors: Saeed Alshahrani, Sharon Barone, Kamyar Zahedi, Robert M. Rapoport, Min Jiang, Michelle Nieman, Andrea L. Meredith, John N. Lorenz, Jack Rubinstein, Manoocher SoleimaniAbstract:(a) M-mode images of cardiac function of WT and Pendrin/NCC dKO mice before and after HCTZ. (b) The examination of cardiac index as measured by echocardiography does not demonstrate any significant reduction in cardiac output of Pendrin/NCC dKO mice after HCTZ treatment (n = 4 each group).
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Original Article Deletion of the Cl2/HCO3
2016Co-Authors: Sharon Barone, Hassane Amlal, Manoocher SoleimaniAbstract:Background. The epithelial calcium channel (ECaC) (TRPV5) and the Cl/HCO3 exchanger Pendrin (SLC26A4) are expressed on the apical membrane of tubular cells in the distal nephron and play essential roles in calcium re-absorption and bicarbonate secretion, respectively, in the kidney. Methods. A combination of functional and molecular biol-ogy techniques were employed to examine the role of Pendrin deletion in calcium excretion. Results. Here, we demonstrate that deletion of Pendrin causes acidic urine [urine pH 4.9 in knockout (KO) versus 5.9 in wild-type (WT) mice, P < 0.03)] and downregulates the calcium-absorbing molecules ECaC and Na/Ca ex-changer in the kidney, as shown by northern hybridization, immunoblot analysis and/or immunofluorescent labeling. These changes were associated with a ~100 % increase in 24-h urine calcium excretion in Pendrin null mice. Subject-ing the Pendrin WT and KO mice to oral bicarbonate loading for 12 days increased the urine pH to ~8 in both genotypes, normalized the expression of ECaC and Na/Ca exchanger and reduced the urine calcium excretion in Pendrin-null mice to levels comparable to WT mice. Conclusions. We suggest that Pendrin dysfunction should be suspected and investigated in humans with an otherwise unexplained acidic urine and hypercalciuria
Kamyar Zahedi - One of the best experts on this subject based on the ideXlab platform.
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Probenecid Pre-treatment Downregulates the Kidney Cl-/HCO3- Exchanger (Pendrin) and Potentiates Hydrochlorothiazide-Induced Diuresis
Frontiers Media S.A., 2018Co-Authors: Manoocher Soleimani, Sharon Barone, Kamyar Zahedi, Marybeth BrooksAbstract:Background: Probenecid is a uricosuric agent that in addition to exerting a positive ionotropic effect in the heart, blocks the ATP transporter Pannexin 1 and inhibits the Cl-/HCO3- exchanger, Pendrin. In the kidney, Pendrin blunts the loss of salt wasting secondary to the inhibition of the thiazide-sensitive Na+-Cl- co-transporter (NCC/SLC12A3).Hypothesis: Pre-treatment with probenecid down-regulates Pendrin; therefore, leaving NCC as the main salt absorbing transporter in the distal nephron, and hence enhances the hydrochlorothiazide (HCTZ)-induced diuresis.Methods: Daily balance studies, blood and urine chemical analysis, immunofluorescence, as well as western and northern blot analyses were utilized to examine the effects of probenecid alone (at 250 mg/kg/day) or in combination with HCTZ (at 40 mg/kg/day) on kidney function and on salt and water transporters in the collecting duct.Results: Male Sprague Dawley rats were subjected to three different protocols: (1) HCTZ for 4 days, (2) probenecid for 10 days, and (3) primed with probenecid for 6 days followed by probenecid and HCTZ for 4 additional days. Treatment protocol 1 (HCTZ for 4 days) only mildly increased the urine volume (U Vol) from a baseline of 9.8–13.4 ml/day. In response to treatment protocol 2 (probenecid for 10 days), U Vol increased to 15.9 ml/24 h. Treatment protocol 3 (probenecid for 6 days followed by probenecid and HCTZ for 4 additional days) increased the U Vol to 42.9 ml/day on day 4 of co-treatment with HCTZ and probenecid (compared to probenecid p = 0.003, n = 5 or HCTZ alone p = 0.001, n = 5). Probenecid treatment at 250 mg/kg/day downregulated the expression of Pendrin and led to a decrease in AQP2 expression. Enhanced diuresis by probenecid plus HCTZ was not associated with volume depletion.Conclusion: Probenecid pre-treatment downregulates Pendrin and robustly enhances diuresis by HCTZ-mediated NCC inhibition in kidney
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Intravascular volume depletion in Pendrin/NCC dKO mice.
2017Co-Authors: Saeed Alshahrani, Sharon Barone, Kamyar Zahedi, Robert M. Rapoport, Min Jiang, Michelle Nieman, Andrea L. Meredith, John N. Lorenz, Jack Rubinstein, Manoocher SoleimaniAbstract:(a) Northern hybridization shows a significant enhancement in mRNA expression levels of renin in kidneys of Pendrin/NCC dKO mice compared to WT, Pendrin KO and NCC KO. (b) Immunofluorescent microscopic analysis of kidney sections indicates that the expression of renin is significantly up regulated in Pendrin/NCC dKO, but not in WT mice. (c) Western blots confirmed the significant increase in renin expression in Pendrin/NCC dKO kidney vs WT. (d) Olmesartan (1 mg/kg) treatment causes a more significant reduction in the systolic BP of Pendrin/NCC dKO mice compared to WT mice, (n = 4 each group); paired t-test * P
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Effects of HCTZ on Pendrin/NCC dKO mice: Role of volume depletion.
2017Co-Authors: Saeed Alshahrani, Sharon Barone, Kamyar Zahedi, Robert M. Rapoport, Min Jiang, Michelle Nieman, Andrea L. Meredith, John N. Lorenz, Jack Rubinstein, Manoocher SoleimaniAbstract:(a) The systolic BP of Pendrin/NCC dKO mice dropped below detectable levels at 1 and 3 hours after HCTZ treatment but returned to baseline levels at 6 and 24 hours later; the systolic BP of WT mice was not significantly affected by HCTZ (#; below detectable level; n = 4). (b) Baseline (BL) blood pressure of Pendrin/NCC dKO mice and WT mice was measured on normal (1% NaCl) diet. Then, mice were placed on high salt (7% NaCl) diets for up to 14 days. On day 14, animals’ baseline (BL) blood pressure was measured and then treated with HCTZ, and their BP was measured at 1, 3, 6, and 24 hours (h). The effect of HCTZ is abrogated in euvolemic Pendrin/NCC dKO mice. (c) Treatment with a high salt diet reduces the renal expression of renin in Pendrin/NCC dKO mice, indicating the correction of the volume depletion (n = 3).
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Echocardiography in anesthetized WT and Pendrin/NCC dKO mice before and after HCTZ.
2017Co-Authors: Saeed Alshahrani, Sharon Barone, Kamyar Zahedi, Robert M. Rapoport, Min Jiang, Michelle Nieman, Andrea L. Meredith, John N. Lorenz, Jack Rubinstein, Manoocher SoleimaniAbstract:(a) M-mode images of cardiac function of WT and Pendrin/NCC dKO mice before and after HCTZ. (b) The examination of cardiac index as measured by echocardiography does not demonstrate any significant reduction in cardiac output of Pendrin/NCC dKO mice after HCTZ treatment (n = 4 each group).
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prostaglandin e2 mediated increase in calcium and phosphate excretion in a mouse model of distal nephron salt wasting
PLOS ONE, 2016Co-Authors: Manoocher Soleimani, Sharon Barone, Kamyar Zahedi, Marybeth Brooks, Saeed Alshahrani, Francis X Mccormack, Roger D SmithAbstract:Contribution of salt wasting and volume depletion to the pathogenesis of hypercalciuria and hyperphosphaturia is poorly understood. Pendrin/NCC double KO (Pendrin/NCC-dKO) mice display severe salt wasting under basal conditions and develop profound volume depletion, prerenal renal failure, and metabolic alkalosis and are growth retarded. Microscopic examination of the kidneys of Pendrin/NCC-dKO mice revealed the presence of calcium phosphate deposits in the medullary collecting ducts, along with increased urinary calcium and phosphate excretion. Confirmatory studies revealed decreases in the expression levels of sodium phosphate transporter-2 isoforms a and c, increases in the expression of cytochrome p450 family 4a isotypes 12 a and b, as well as prostaglandin E synthase 1, and cyclooxygenases 1 and 2. Pendrin/NCC-dKO animals also had a significant increase in urinary prostaglandin E2 (PGE-2) and renal content of 20-hydroxyeicosatetraenoic acid (20-HETE) levels. Pendrin/NCC-dKO animals exhibit reduced expression levels of the sodium/potassium/2chloride co-transporter 2 (NKCC2) in their medullary thick ascending limb. Further assessment of the renal expression of NKCC2 isoforms by quantitative real time PCR (qRT-PCR) reveled that compared to WT mice, the expression of NKCC2 isotype F was significantly reduced in Pendrin/NCC-dKO mice. Provision of a high salt diet to rectify volume depletion or inhibition of PGE-2 synthesis by indomethacin, but not inhibition of 20-HETE generation by HET0016, significantly improved hypercalciuria and salt wasting in Pendrin/NCC dKO mice. Both high salt diet and indomethacin treatment also corrected the alterations in NKCC2 isotype expression in Pendrin/NCC-dKO mice. We propose that severe salt wasting and volume depletion, irrespective of the primary originating nephron segment, can secondarily impair the reabsorption of salt and calcium in the thick ascending limb of Henle and/or proximal tubule, and reabsorption of sodium and phosphate in the proximal tubule via processes that are mediated by PGE-2.
Susan M. Wall - One of the best experts on this subject based on the ideXlab platform.
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the renal physiology of Pendrin positive intercalated cells
Physical Review, 2020Co-Authors: Susan M. Wall, Jill W Verlander, Cesar A RomeroAbstract:Intercalated cells (ICs) are found in the connecting tubule and the collecting duct. Of the three IC subtypes identified, type B intercalated cells are one of the best characterized and known to mediate Cl- absorption and HCO3- secretion, largely through the anion exchanger Pendrin. This exchanger is thought to act in tandem with the Na+-dependent Cl-/HCO3- exchanger, NDCBE, to mediate net NaCl absorption. Pendrin is stimulated by angiotensin II and aldosterone administration via the angiotensin type 1a and the mineralocorticoid receptors, respectively. It is also stimulated in models of metabolic alkalosis, such as with NaHCO3 administration. In some rodent models, Pendrin-mediated HCO3- secretion modulates acid-base balance. However, of probably more physiological or clinical significance is the role of these Pendrin-positive ICs in blood pressure regulation, which occurs, at least in part, through Pendrin-mediated renal Cl- absorption, as well as their effect on the epithelial Na+ channel, ENaC. Aldosterone stimulates ENaC directly through principal cell mineralocorticoid hormone receptor (ligand) binding and also indirectly through its effect on Pendrin expression and function. In so doing, Pendrin contributes to the aldosterone pressor response. Pendrin may also modulate blood pressure in part through its action in the adrenal medulla, where it modulates the release of catecholamines, or through an indirect effect on vascular contractile force. In addition to its role in Na+ and Cl- balance, Pendrin affects the balance of other ions, such as K+ and I-. This review describes how aldosterone and angiotensin II-induced signaling regulate Pendrin and the contribution of Pendrin-positive ICs in the kidney to distal nephron function and blood pressure.
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aldosterone regulates Pendrin and epithelial sodium channel activity through intercalated cell mineralocorticoid receptor dependent and independent mechanisms over a wide range in serum potassium
Journal of The American Society of Nephrology, 2020Co-Authors: Truyen D Pham, Jill W Verlander, Douglas C. Eaton, Yoskaly Lazofernandez, Cesar A Romero, Yanhua Wang, Qiang Yue, Chao Chen, Monika Thumova, Susan M. WallAbstract:Background Aldosterone activates the intercalated cell mineralocorticoid receptor, which is enhanced with hypokalemia. Whether this receptor directly regulates the intercalated cell chloride/bicarbonate exchanger Pendrin is unclear, as are potassium's role in this response and the receptor's effect on intercalated and principal cell function in the cortical collecting duct (CCD). Methods We measured CCD chloride absorption, transepithelial voltage, epithelial sodium channel activity, and Pendrin abundance and subcellular distribution in wild-type and intercalated cell-specific mineralocorticoid receptor knockout mice. To determine if the receptor directly regulates Pendrin, as well as the effect of serum aldosterone and potassium on this response, we measured Pendrin label intensity and subcellular distribution in wild-type mice, knockout mice, and receptor-positive and receptor-negative intercalated cells from the same knockout mice. Results Ablation of the intercalated cell mineralocorticoid receptor in CCDs from aldosterone-treated mice reduced chloride absorption and epithelial sodium channel activity, despite principal cell mineralocorticoid receptor expression in the knockout mice. With high circulating aldosterone, intercalated cell mineralocorticoid receptor gene ablation directly reduced Pendrin's relative abundance in the apical membrane region and Pendrin abundance per cell whether serum potassium was high or low. Intercalated cell mineralocorticoid receptor ablation blunted, but did not eliminate, aldosterone's effect on Pendrin total and apical abundance and subcellular distribution. Conclusions With high circulating aldosterone, intercalated cell mineralocorticoid receptor ablation reduces chloride absorption in the CCD and indirectly reduces principal cell epithelial sodium channel abundance and function. This receptor directly regulates Pendrin's total abundance and its relative abundance in the apical membrane region over a wide range in serum potassium concentration. Aldosterone regulates Pendrin through mechanisms both dependent and independent of the IC MR receptor.
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Renal intercalated cells and blood pressure regulation
Kidney research and clinical practice, 2017Co-Authors: Susan M. WallAbstract:Type B and non-A, non-B intercalated cells are found within the connecting tubule and the cortical collecting duct. Of these cell types, type B intercalated cells are known to mediate Cl- absorption and HCO3- secretion largely through Pendrin-dependent Cl-/HCO3- exchange. This exchange is stimulated by angiotensin II administration and is also stimulated in models of metabolic alkalosis, for instance after aldosterone or NaHCO3 administration. In some rodent models, Pendrin-mediated HCO3- secretion modulates acid-base balance. However, the role of Pendrin in blood pressure regulation is likely of more physiological or clinical significance. Pendrin regulates blood pressure not only by mediating aldosterone-sensitive Cl- absorption, but also by modulating the aldosterone response for epithelial Na+ channel (ENaC)-mediated Na+ absorption. Pendrin regulates ENaC through changes in open channel of probability, channel surface density, and channels subunit total protein abundance. Thus, aldosterone stimulates ENaC activity through both direct and indirect effects, the latter occurring through its stimulation of Pendrin expression and function. Therefore, Pendrin contributes to the aldosterone pressor response. Pendrin may also modulate blood pressure in part through its action in the adrenal medulla, where it modulates the release of catecholamines, or through an indirect effect on vascular contractile force. This review describes how aldosterone and angiotensin II-induced signaling regulate Pendrin and the contributory role of Pendrin in distal nephron function and blood pressure.
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Pendrin localizes to the adrenal medulla where it modulates catecholamine release 701 1
The FASEB Journal, 2014Co-Authors: Yoskaly Lazofernandez, Jill W Verlander, Greti Aguilera, William H Beierwaltes, Karel Pacak, Paul M Plotsky, Susan M. WallAbstract:Pendrin is an aldosterone-sensitive, Na+-independent Cl-/HCO3- exchanger expressed in intercalated cells within the renal cortex where it modulates blood pressure. Since Pendrin gene ablation stimulates the release of renin, but not aldosterone, we hypothesized that Pendrin is expressed in the adrenal gland and modulates adrenal function. Thus, we examined rat and mouse adrenal Pendrin mRNA and protein abundance by PCR, immunoblot and immunohistochemistry and examined adrenal responses in wild type and Pendrin null mice. Pendrin protein was detected in adrenal lysates from wild type, but not Pendrin null mice. In both mice and rats, we observed Pendrin mRNA and protein in the adrenal medulla but not in the adrenal cortex. Since the adrenal medulla produces catecholamines, further experiments examined plasma epinephrine responses to 5 and 20 min of immobilization stress in wild type and Pendrin null mice. Basal epinephrine concentration was similar in wild type and Pendrin null mice. Immobilization stress ...
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deoxycorticosterone upregulates pds slc26a4 in mouse kidney role of Pendrin in mineralocorticoid induced hypertension
Hypertension, 2003Co-Authors: Jill W Verlander, Kathryn A Hassell, Ines E Royaux, Dawn M Glapion, Mouer Wang, Lorraine A Everett, Eric D Green, Susan M. WallAbstract:Pendrin is an anion exchanger expressed along the apical plasma membrane and apical cytoplasmic vesicles of type B and of non-A, non-B intercalated cells of the distal convoluted tubule, connecting tubule, and cortical collecting duct. Thus, Pds ( Slc26a4 ) is a candidate gene for the putative apical anion-exchange process of the type B intercalated cell. Because apical anion exchange–mediated transport is upregulated with deoxycorticosterone pivalate (DOCP), we tested whether Pds mRNA and protein expression in mouse kidney were upregulated after administration of this aldosterone analogue by using quantitative real-time polymerase chain reaction as well as light and electron microscopic immunolocalization. In kidneys from DOCP-treated mice, Pds mRNA increased 60%, whereas Pendrin protein expression in the apical plasma membrane increased 2-fold in non-A, non-B intercalated cells and increased 6-fold in type B cells. Because Pendrin transports HCO 3 − and Cl − , we tested whether DOCP treatment unmasks abnormalities in acid-base or NaCl balance in Pds (-/- ) mice. In the absence of DOCP, arterial pH, systolic blood pressure, and body weight were similar in Pds (+/+ ) and Pds (-/- ) mice. After DOCP treatment, weight gain and hypertension were observed in Pds (+/+ ) but not in Pds (-/- ) mice. Moreover, after DOCP administration, metabolic alkalosis was more severe in Pds (-/- ) than Pds (+/+ ) mice. We conclude that Pendrin is upregulated with aldosterone analogues and is critical in the pathogenesis of mineralocorticoid-induced hypertension and metabolic alkalosis.
Silvia Dossena - One of the best experts on this subject based on the ideXlab platform.
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Interleukin-Mediated Pendrin Transcriptional Regulation in Airway and Esophageal Epithelia
MDPI AG, 2019Co-Authors: Simone Vanoni, Giada Scantamburlo, Silvia Dossena, Markus Paulmichl, Charity NofzigerAbstract:Pendrin (SLC26A4), a Cl−/anion exchanger, is expressed at high levels in kidney, thyroid, and inner ear epithelia, where it has an essential role in bicarbonate secretion/chloride reabsorption, iodide accumulation, and endolymph ion balance, respectively. Pendrin is expressed at lower levels in other tissues, such as airways and esophageal epithelia, where it is transcriptionally regulated by the inflammatory cytokines interleukin (IL)-4 and IL-13 through a signal transducer and activator of transcription 6 (STAT6)-mediated pathway. In the airway epithelium, increased Pendrin expression during inflammatory diseases leads to imbalances in airway surface liquid thickness and mucin release, while, in the esophageal epithelium, dysregulated Pendrin expression is supposed to impact the intracellular pH regulation system. In this review, we discuss some of the recent findings on interleukin-mediated transcriptional regulation of Pendrin and how this dysregulation impacts airway and esophagus epithelial homeostasis during inflammatory diseases
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Interleukin-4 Induces CpG Site-Specific Demethylation of the Pendrin Promoter in Primary Human Bronchial Epithelial Cells.
Cellular physiology and biochemistry : international journal of experimental cellular physiology biochemistry and pharmacology, 2017Co-Authors: Giada Scantamburlo, Simone Vanoni, Silvia Dossena, Selma M. Soyal, Emanuele Bernardinelli, Davide Antonio Civello, Wolfgang Patsch, Markus Paulmichl, Charity NofzigerAbstract:Pendrin is upregulated in bronchial epithelial cells following IL-4 stimulation via binding of STAT6 to an N 4 GAS motif. Basal CpG methylation of the Pendrin promoter is cell-specific. We studied if a correlation exists between IL-4 sensitivity and the CpG methylation status of the Pendrin promoter in human bronchial epithelial cell models. Methods: Real-time PCR and pyrosequencing were used to respectively quantify Pendrin mRNA levels and methylation of Pendrin promoter, with and without IL-4 stimulation, in healthy and diseased primary HBE cells, as well as NCI-H292 cells. Results: Increases in Pendrin mRNA after IL-4 stimulation was more robust in NCI-H292 cells than in primary cells. The amount of gDNA methylated varied greatly between the cell types. In particular, CpG site 90 located near the N 4 GAS motif was highly methylated in the primary cells. An additional CpG site (90bis), created by a SNP, was found only in the primary cells. IL-4 stimulation resulted in dramatic demethylation of CpG sites 90 and 90bis in the primary cells. Conclusions: IL-4 induces demethylation of specific CpG sites within the Pendrin promoter. These epigenetic alterations are cell type specific, and may in part dictate Pendrin mRNA transcription.
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Interleukin-13 increases Pendrin abundance to the cell surface in bronchial NCI-H292 cells via Rho/actin signaling
'Springer Science and Business Media LLC', 2017Co-Authors: Annamaria Russo, Silvia Dossena, Markus Paulmichl, Charity Nofziger, Marianna Ranieri, Annarita Di Mise, Tommaso Pellegrino, Emilia Furia, Lucantonio Debellis, Giovanna ValentiAbstract:Interleukin-13 (IL13) is a major player in the development of airway hyperresponsiveness in several respiratory disorders. Emerging data suggest that an increased expression of Pendrin in airway epithelia is associated with elevated airway hyper-reactivity in asthma. Here, we investigate the effect of IL13 on Pendrin localization and function using bronchiolar NCI-H292 cells. The data obtained revealed that IL13 increases the cell surface expression of Pendrin. This effect was paralleled by a significant increase in the intracellular pH, possibly via indirect stimulation of NHE. IL13 effect on Pendrin localization and intracellular pH were reversed by theophylline, a bronchodilator compound used to treat asthma. IL13 upregulated RhoA activity, a crucial protein controlling actin dynamics, via G-alpha-13. Specifically, IL13 stabilized actin cytoskeleton and promoted co-localization and a direct molecular interaction between Pendrin and F-actin in the plasma membrane region. These effects were reversed following exposure of cells to theophylline. Selective inhibition of Rho kinase, a downstream effector of Rho, reduced the IL13-dependent cell surface expression of Pendrin. Together, these data indicate that IL13 increases Pendrin abundance to the cell surface via Rho/actin signaling, an effect reversed by theophylline
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Effect of Known Inhibitors of Ion Transport on Pendrin (SLC26A4) Activity in a Human Kidney Cell Line
Karger Publishers, 2016Co-Authors: Emanuele Bernardinelli, Markus Paulmichl, Charity Nofziger, Roberta Costa, Silvia DossenaAbstract:Background/Aims: Pendrin is a Cl-/I-/HCO3- exchanger playing a fundamental role in controlling blood pressure and airway function, therefore representing an attractive target for the treatment of hypertensive states and respiratory distresses. A review of the literature regarding the ability of some compounds (namely several known inhibitors of ion transport) to block Pendrin activity revealed discordant findings. These incongruous findings may be due, in part, to the concentration of compound and/or the nature of the model system used in the study. Methods: Pendrin activity was evaluated by measuring Pendrin-dependent iodide influx following overexpression of the transporter in a human kidney cell line, in the presence of selected test compounds or the respective vehicles. Results: Pendrin activity was significantly hampered by 0.1 mM 5-nitro-2-[(3-phenylpropyl)amino]benzoic acid (NPPB), niflumic acid and tenidap, but was resistant to 0.1 mM 4, 4′-diisothiocyano-2, 2′-stilbene-disulfonic acid (DIDS), furosemide and probenecid. Conclusions: The results of the present study indicate that clinically effective non-steroidal anti-inflammatory drugs (niflumic acid and tenidap) directly inhibit Pendrin activity
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Reduction of Cellular Expression Levels Is a Common Feature of Functionally Affected Pendrin (SLC26A4) Protein Variants
Molecular Medicine, 2016Co-Authors: Vanessa C S Moraes, Emanuele Bernardinelli, Markus Paulmichl, Charity Nofziger, Nathalia Zocal, Jhonathan A Fernandez, Arthur M Castilho, Edi L Sartorato, Silvia DossenaAbstract:Sequence alterations in the Pendrin gene ( SLC26A4 ) leading to functionally affected protein variants are frequently involved in the pathogenesis of syndromic and nonsyndromic deafness. Considering the high number of SLC26A4 sequence alterations reported to date, discriminating between functionally affected and unaffected Pendrin protein variants is essential in contributing to determine the genetic cause of deafness in a given patient. In addition, identifying molecular features common to the functionally affected protein variants can be extremely useful to design future molecule-directed therapeutic approaches. Here we show the functional and molecular characterization of six previously uncharacterized Pendrin protein variants found in a cohort of 58 Brazilian deaf patients. Two variants (p.T193I and p.L445W) were undetectable in the plasma membrane, completely retained in the endoplasmic reticulum and showed no transport function; four (p.P142L, p.G149R, p.C282Y and p.Q413R) showed reduced function and significant, although heterogeneous, expression levels in the plasma membrane. Importantly, total expression levels of all of the functionally affected protein variants were significantly reduced with respect to the wild-type and a fully functional variant (p.R776C), regardless of their subcellular localization. Interestingly, reduction of expression may also reduce the transport activity of variants with an intrinsic gain of function (p.Q413R). As reduction of overall cellular abundance was identified as a common molecular feature of Pendrin variants with affected function, the identification of strategies to prevent reduction in expression levels may represent a crucial step of potential future therapeutic interventions aimed at restoring the transport activity of dysfunctional Pendrin variants.
