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Atsuhiro Ichihara - One of the best experts on this subject based on the ideXlab platform.
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collecting duct Prorenin Receptor knockout reduces renal function increases sodium excretion and mitigates renal responses in ang ii induced hypertensive mice
American Journal of Physiology-renal Physiology, 2017Co-Authors: Minolfa C Prieto, Carla B Rosales, Mykola Mamenko, Virginia Reverte, Marta Kuczeriszka, Luciana C Veiras, Matthew Mclellan, Oliver O Gentile, Behrana V Jensen, Atsuhiro IchiharaAbstract:Augmented intratubular angiotensin (ANG) II is a key determinant of enhanced distal Na+ reabsorption via activation of epithelial Na+ channels (ENaC) and other transporters, which leads to the deve...
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renal tubular epithelial cell Prorenin Receptor regulates blood pressure and sodium transport
American Journal of Physiology-renal Physiology, 2016Co-Authors: Nirupama Ramkumar, James D Stockand, Atsuhiro Ichihara, Elena Mironova, Deborah Stuart, Nikita Abraham, Shuping Wang, Vladislav Bugay, Donald E KohanAbstract:The physiological significance of the renal tubular Prorenin Receptor (PRR) has been difficult to elucidate due to developmental abnormalities associated with global or renal-specific PRR knockout (KO). We recently developed an inducible renal tubule-wide PRR KO using the Pax8/LC1 transgenes and demonstrated that disruption of renal tubular PRR at 1 mo of age caused no renal histological abnormalities. Here, we examined the role of renal tubular PRR in blood pressure (BP) regulation and Na(+) excretion and investigated the signaling mechanisms by which PRR regulates Na(+) balance. No detectable differences in BP were observed between control and PRR KO mice fed normal- or low-Na(+) diets. However, compared with controls, PRR KO mice had elevated plasma renin concentration and lower cumulative Na(+) balance with normal- and low-Na(+) intake. PRR KO mice had an attenuated hypertensive response and reduced Na(+) retention following angiotensin II (ANG II) infusion. Furthermore, PRR KO mice had significantly lower epithelial Na(+) channel (ENaC-α) expression. Treatment with mouse Prorenin increased, while PRR antagonism decreased, ENaC activity in isolated split-open collecting ducts (CD). The Prorenin effect was prevented by protein kinase A and Akt inhibition, but unaffected by blockade of AT1, ERK1/2, or p38 MAPK pathways. Taken together, these data indicate that renal tubular PRR, likely via direct Prorenin/renin stimulation of PKA/Akt-dependent pathways, stimulates CD ENaC activity. Absence of renal tubular PRR promotes Na(+) wasting and reduces the hypertensive response to ANG II.
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abstract 021 nephron specific deletion of the Prorenin Receptor modulates blood pressure and urinary na excretion
Hypertension, 2015Co-Authors: Nirupama Ramkumar, James D Stockand, Atsuhiro Ichihara, Elena Mironova, Deborah Stuart, Shuping Wang, Vladislav Bugay, Mykola Mamenko, Oleh Pochynyuk, Donald E KohanAbstract:The nephron Prorenin Receptor (PRR) may modulate blood pressure (BP) and Na+ balance. Since previous models of PRR knockout (KO) mice had early lethality and/or structural defects, we developed an inducible nephron-wide PRR KO using the Pax8/LC1 transgenes. Disruption of nephron PRR at 1 month of age caused no renal histological abnormalities. On a normal Na+ diet, wild-type (WT) and PRR KO mice had similar BP and Na+ excretion. However, PRR KO mice had elevated PRC (KO- 377 ± 77 vs WT- 127 ± 19 ng Ang-I/ml/hr) and a 50% decrease in renal ENaC-α protein. Protein levels of NHE3, NKCC2, NCC and ENaC-β/γ were similar between the two groups. Treatment with mouse Prorenin (10 nM for 30 min) increased ENaC channel number by 2-fold, but not open probability, in isolated split-open cortical collecting ducts (CCD) from WT mice; this was prevented by Akt inhibition (A6730) but unaffected by blockade of AT-1 (losartan), ERK1/2 (U0126) or p38 MAPK (SB203580). Addition of Prorenin (10 nM) did not change isolated CCD [Ca2+]i as assessed by Fura-2 loading (10 min exposure with readings every 3 sec). On a low Na+ diet, PRR KO mice had increased Na+ excretion (Day 2: KO - 66 ± 11 vs WT- 42 ± 6 μmol/day; Day 6: KO - 39 ± 4 vs ET- 23 ± 4 μmol/day) however, no differences in BP were observed. PRC was elevated in PRR KO mice on a low Na+ diet (KO- 384 ± 40 vs WT-174 ± 12 ng/ Ang-I/ml/hr). PRR KO mice had an attenuated hypertensive response to Angiotensin-II (Ang-II) infusion at 600 ng/Kg/min for 2 weeks (MAP: KO - 117 ± 4 vs WT - 133 ± 4 mm Hg over the course of Ang-II infusion). Urinary Na+ excretion was elevated in Ang-II treated PRR KO mice as compared to WT mice (KO-344 ± 14 vs WT-268 ±30 μmol/day). Taken together, these data indicate that nephron PRR, likely via direct Prorenin/renin stimulation of an Akt-dependent pathway, stimulates CCD ENaC activity. Absence of nephron PRR promotes Na+ wasting and reduces the hypertensive response to Ang-II.
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nephron specific deletion of the Prorenin Receptor causes a urine concentration defect
American Journal of Physiology-renal Physiology, 2015Co-Authors: Nirupama Ramkumar, Atsuhiro Ichihara, Deborah Stuart, Shuping Wang, Matias Calquin, Syed Quadri, Alfred N Van Hoek, Helmy M Siragy, Donald E KohanAbstract:The Prorenin Receptor (PRR), a recently discovered component of the renin-angiotensin system, is expressed in the nephron in general and the collecting duct in particular. However, the physiologica...
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deletion of the Prorenin Receptor from the ureteric bud causes renal hypodysplasia
PLOS ONE, 2013Co-Authors: Renfang Song, Atsuhiro Ichihara, Graeme Preston, Ihor V. YosypivAbstract:The role of the Prorenin Receptor (PRR) in the regulation of ureteric bud (UB) branching morphogenesis is unknown. Here, we investigated whether PRR acts specifically in the UB to regulate UB branching, kidney development and function. We demonstrate that embryonic (E) day E13.5 mouse metanephroi, isolated intact E11.5 UBs and cultured UB cells express PRR mRNA. To study its role in UB development, we conditionally ablated PRR in the developing UB (PRRUB−/−) using Hoxb7Cre mice. On E12.5, PRRUB−/− mice had decreased UB branching and increased UB cell apoptosis. These defects were associated with decreased expression of Ret, Wnt11, Etv4/Etv5, and reduced phosphorylation of Erk1/2 in the UB. On E18.5, mutants had marked kidney hypoplasia, widespread apoptosis of medullary collecting duct cells and decreased expression of Foxi1, AE1 and H+-ATPase α4 mRNA. Ultimately, they developed occasional small cysts in medullary collecting ducts and had decreased nephron number. To test the functional consequences of these alterations, we determined the ability of PRRUB−/− mice to acidify and concentrate the urine on postnatal (P) day P30. PRRUB−/− mice were polyuric, had lower urine osmolality and a higher urine pH following 48 hours of acidic loading with NH4Cl. Taken together, these data show that PRR present in the UB epithelia performs essential functions during UB branching morphogenesis and collecting duct development via control of Ret/Wnt11 pathway gene expression, UB cell survival, activation of Erk1/2, terminal differentiation and function of collecting duct cells needed for maintaining adequate water and acid-base homeostasis. We propose that mutations in PRR could possibly cause renal hypodysplasia and renal tubular acidosis in humans.
Donald E Kohan - One of the best experts on this subject based on the ideXlab platform.
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abstract 095 mutation in the furin cleavage site of the Prorenin Receptor attenuates angiotensin ii induced hypertension and albuminuria
Hypertension, 2019Co-Authors: Nirupama Ramkumar, Deborah Stuart, Will Wheatley, Donald E KohanAbstract:Cleavage of the extra-cellular domain of the (pro)renin Receptor (PRR) yields a soluble fragment (sPRR) which can promote angiotensin-II (Ang-II) formation. Although alterations in plasma sPRR leve...
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nephron Prorenin Receptor deficiency alters renal medullary endothelin 1 and endothelin Receptor expression
Physiological Research, 2018Co-Authors: Nirupama Ramkumar, Deborah Stuart, Nikita Abraham, Donald E KohanAbstract:The endothelin (ET) and Prorenin/renin/Prorenin Receptor (PRR) systems have opposing physiological effects on collecting duct (CD) salt and water reabsorption. It is unknown if the CD ET and renin/PRR systems interact, hence we examined the effects of deleting CD renin or nephron PRR on CD ET system components. PRR knockout (KO) mice were polyuric and had markedly increased urinary ET-1 and inner medullary CD (IMCD) ET-1 mRNA. PRR KO mice had greatly increased IMCD ETA Receptor mRNA and protein, while ETB mRNA and protein were decreased. Water loaded wild-type mice with similar polyuria as PRR KO mice had modestly increased urinary ET-1 excretion and inner medullary ET-1 mRNA, while inner medullary ETA and ETB mRNA or protein expression were unaffected. In contrast to PRR KO, CD Prorenin/renin KO did not alter ET system components. Taken together, these results suggest that the nephron PRR is involved in regulating CD ET system expression, but this effect may be independent of CD-derived renin.
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renal tubular epithelial cell Prorenin Receptor regulates blood pressure and sodium transport
American Journal of Physiology-renal Physiology, 2016Co-Authors: Nirupama Ramkumar, James D Stockand, Atsuhiro Ichihara, Elena Mironova, Deborah Stuart, Nikita Abraham, Shuping Wang, Vladislav Bugay, Donald E KohanAbstract:The physiological significance of the renal tubular Prorenin Receptor (PRR) has been difficult to elucidate due to developmental abnormalities associated with global or renal-specific PRR knockout (KO). We recently developed an inducible renal tubule-wide PRR KO using the Pax8/LC1 transgenes and demonstrated that disruption of renal tubular PRR at 1 mo of age caused no renal histological abnormalities. Here, we examined the role of renal tubular PRR in blood pressure (BP) regulation and Na(+) excretion and investigated the signaling mechanisms by which PRR regulates Na(+) balance. No detectable differences in BP were observed between control and PRR KO mice fed normal- or low-Na(+) diets. However, compared with controls, PRR KO mice had elevated plasma renin concentration and lower cumulative Na(+) balance with normal- and low-Na(+) intake. PRR KO mice had an attenuated hypertensive response and reduced Na(+) retention following angiotensin II (ANG II) infusion. Furthermore, PRR KO mice had significantly lower epithelial Na(+) channel (ENaC-α) expression. Treatment with mouse Prorenin increased, while PRR antagonism decreased, ENaC activity in isolated split-open collecting ducts (CD). The Prorenin effect was prevented by protein kinase A and Akt inhibition, but unaffected by blockade of AT1, ERK1/2, or p38 MAPK pathways. Taken together, these data indicate that renal tubular PRR, likely via direct Prorenin/renin stimulation of PKA/Akt-dependent pathways, stimulates CD ENaC activity. Absence of renal tubular PRR promotes Na(+) wasting and reduces the hypertensive response to ANG II.
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abstract 021 nephron specific deletion of the Prorenin Receptor modulates blood pressure and urinary na excretion
Hypertension, 2015Co-Authors: Nirupama Ramkumar, James D Stockand, Atsuhiro Ichihara, Elena Mironova, Deborah Stuart, Shuping Wang, Vladislav Bugay, Mykola Mamenko, Oleh Pochynyuk, Donald E KohanAbstract:The nephron Prorenin Receptor (PRR) may modulate blood pressure (BP) and Na+ balance. Since previous models of PRR knockout (KO) mice had early lethality and/or structural defects, we developed an inducible nephron-wide PRR KO using the Pax8/LC1 transgenes. Disruption of nephron PRR at 1 month of age caused no renal histological abnormalities. On a normal Na+ diet, wild-type (WT) and PRR KO mice had similar BP and Na+ excretion. However, PRR KO mice had elevated PRC (KO- 377 ± 77 vs WT- 127 ± 19 ng Ang-I/ml/hr) and a 50% decrease in renal ENaC-α protein. Protein levels of NHE3, NKCC2, NCC and ENaC-β/γ were similar between the two groups. Treatment with mouse Prorenin (10 nM for 30 min) increased ENaC channel number by 2-fold, but not open probability, in isolated split-open cortical collecting ducts (CCD) from WT mice; this was prevented by Akt inhibition (A6730) but unaffected by blockade of AT-1 (losartan), ERK1/2 (U0126) or p38 MAPK (SB203580). Addition of Prorenin (10 nM) did not change isolated CCD [Ca2+]i as assessed by Fura-2 loading (10 min exposure with readings every 3 sec). On a low Na+ diet, PRR KO mice had increased Na+ excretion (Day 2: KO - 66 ± 11 vs WT- 42 ± 6 μmol/day; Day 6: KO - 39 ± 4 vs ET- 23 ± 4 μmol/day) however, no differences in BP were observed. PRC was elevated in PRR KO mice on a low Na+ diet (KO- 384 ± 40 vs WT-174 ± 12 ng/ Ang-I/ml/hr). PRR KO mice had an attenuated hypertensive response to Angiotensin-II (Ang-II) infusion at 600 ng/Kg/min for 2 weeks (MAP: KO - 117 ± 4 vs WT - 133 ± 4 mm Hg over the course of Ang-II infusion). Urinary Na+ excretion was elevated in Ang-II treated PRR KO mice as compared to WT mice (KO-344 ± 14 vs WT-268 ±30 μmol/day). Taken together, these data indicate that nephron PRR, likely via direct Prorenin/renin stimulation of an Akt-dependent pathway, stimulates CCD ENaC activity. Absence of nephron PRR promotes Na+ wasting and reduces the hypertensive response to Ang-II.
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nephron specific deletion of the Prorenin Receptor causes a urine concentration defect
American Journal of Physiology-renal Physiology, 2015Co-Authors: Nirupama Ramkumar, Atsuhiro Ichihara, Deborah Stuart, Shuping Wang, Matias Calquin, Syed Quadri, Alfred N Van Hoek, Helmy M Siragy, Donald E KohanAbstract:The Prorenin Receptor (PRR), a recently discovered component of the renin-angiotensin system, is expressed in the nephron in general and the collecting duct in particular. However, the physiologica...
Nirupama Ramkumar - One of the best experts on this subject based on the ideXlab platform.
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abstract 095 mutation in the furin cleavage site of the Prorenin Receptor attenuates angiotensin ii induced hypertension and albuminuria
Hypertension, 2019Co-Authors: Nirupama Ramkumar, Deborah Stuart, Will Wheatley, Donald E KohanAbstract:Cleavage of the extra-cellular domain of the (pro)renin Receptor (PRR) yields a soluble fragment (sPRR) which can promote angiotensin-II (Ang-II) formation. Although alterations in plasma sPRR leve...
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collecting duct principal but not intercalated cell Prorenin Receptor regulates renal sodium and water excretion
American Journal of Physiology-renal Physiology, 2018Co-Authors: Nirupama Ramkumar, Elena Mironova, Deborah Stuart, Nikita Abraham, Yang Gao, Shuping Wang, Jayalakshmi Lakshmipathi, James D StockandAbstract:The collecting duct is the predominant nephron site of Prorenin and Prorenin Receptor (PRR) expression. We previously demonstrated that the collecting duct PRR regulates epithelial Na+ channel (ENa...
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nephron Prorenin Receptor deficiency alters renal medullary endothelin 1 and endothelin Receptor expression
Physiological Research, 2018Co-Authors: Nirupama Ramkumar, Deborah Stuart, Nikita Abraham, Donald E KohanAbstract:The endothelin (ET) and Prorenin/renin/Prorenin Receptor (PRR) systems have opposing physiological effects on collecting duct (CD) salt and water reabsorption. It is unknown if the CD ET and renin/PRR systems interact, hence we examined the effects of deleting CD renin or nephron PRR on CD ET system components. PRR knockout (KO) mice were polyuric and had markedly increased urinary ET-1 and inner medullary CD (IMCD) ET-1 mRNA. PRR KO mice had greatly increased IMCD ETA Receptor mRNA and protein, while ETB mRNA and protein were decreased. Water loaded wild-type mice with similar polyuria as PRR KO mice had modestly increased urinary ET-1 excretion and inner medullary ET-1 mRNA, while inner medullary ETA and ETB mRNA or protein expression were unaffected. In contrast to PRR KO, CD Prorenin/renin KO did not alter ET system components. Taken together, these results suggest that the nephron PRR is involved in regulating CD ET system expression, but this effect may be independent of CD-derived renin.
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renal tubular epithelial cell Prorenin Receptor regulates blood pressure and sodium transport
American Journal of Physiology-renal Physiology, 2016Co-Authors: Nirupama Ramkumar, James D Stockand, Atsuhiro Ichihara, Elena Mironova, Deborah Stuart, Nikita Abraham, Shuping Wang, Vladislav Bugay, Donald E KohanAbstract:The physiological significance of the renal tubular Prorenin Receptor (PRR) has been difficult to elucidate due to developmental abnormalities associated with global or renal-specific PRR knockout (KO). We recently developed an inducible renal tubule-wide PRR KO using the Pax8/LC1 transgenes and demonstrated that disruption of renal tubular PRR at 1 mo of age caused no renal histological abnormalities. Here, we examined the role of renal tubular PRR in blood pressure (BP) regulation and Na(+) excretion and investigated the signaling mechanisms by which PRR regulates Na(+) balance. No detectable differences in BP were observed between control and PRR KO mice fed normal- or low-Na(+) diets. However, compared with controls, PRR KO mice had elevated plasma renin concentration and lower cumulative Na(+) balance with normal- and low-Na(+) intake. PRR KO mice had an attenuated hypertensive response and reduced Na(+) retention following angiotensin II (ANG II) infusion. Furthermore, PRR KO mice had significantly lower epithelial Na(+) channel (ENaC-α) expression. Treatment with mouse Prorenin increased, while PRR antagonism decreased, ENaC activity in isolated split-open collecting ducts (CD). The Prorenin effect was prevented by protein kinase A and Akt inhibition, but unaffected by blockade of AT1, ERK1/2, or p38 MAPK pathways. Taken together, these data indicate that renal tubular PRR, likely via direct Prorenin/renin stimulation of PKA/Akt-dependent pathways, stimulates CD ENaC activity. Absence of renal tubular PRR promotes Na(+) wasting and reduces the hypertensive response to ANG II.
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role of the collecting duct renin angiotensin system in regulation of blood pressure and renal function
Current Hypertension Reports, 2016Co-Authors: Nirupama RamkumarAbstract:Recent evidence suggests that the renal tubular renin angiotensin system regulates urinary Na+ and water excretion and blood pressure. Three key components of the tubular renin angiotensin system, namely renin, Prorenin Receptor, and angiotensin-II type 1 Receptor, are localized to the collecting duct. This system may modulate collecting duct Na+ and water reabsorption via angiotensin-II-dependent and angiotensin-II-independent pathways. Further, the system may be of greatest relevance in hypertensive states and particularly those characterized by high circulating angiotensin-II. In this review, we summarize the current knowledge on the synthesis, regulation, and function of collecting duct-derived renin angiotensin system components and examine recent developments with regard to regulation of blood pressure and renal fluid and Na+ excretion.
Fumiaki Suzuki - One of the best experts on this subject based on the ideXlab platform.
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laughter modulates Prorenin Receptor gene expression in patients with type 2 diabetes
Journal of Psychosomatic Research, 2007Co-Authors: Takashi Hayashi, Fumiaki Suzuki, Uddin Mohammad Nasir, Osamu Urayama, Miyo Hori, Shigeko Sakamoto, Shizuko Iwanaga, Keiko Hayashi, Koichi Kawai, Kazuo MurakamiAbstract:Abstract Objective The purpose of this study was to assess whether laughter influences the expression of the Receptor gene for Prorenin that participates in the progression of diabetic nephropathy. Methods Sixteen normal subjects and 23 patients with type 2 diabetes [12 nephropathy (−) and 11 nephropathy (+)] were recruited to examine the effects of laughter on the modulation of Prorenin Receptor gene expression. After watching a comedy show, laughter-induced changes in the levels of blood Prorenin and the expression of Prorenin Receptor gene were analyzed by an antibody-activating direct enzyme kinetic assay and by reverse transcriptase polymerase chain reaction, respectively. Results In diabetic patients, laughter decreased the level of blood Prorenin [93.4–60.4 ng/l in nephropathy (−) patients, 196.6–166.7 ng/l in nephropathy (+) patients] and up-regulated the Prorenin Receptor gene [1.49-fold in nephropathy (−) patients, 1.46-fold in nephropathy (+) patients]. No significant changes in the expression of this gene were recognized in normal subjects. Conclusion The beneficial effects of laughter on preventing the exacerbation of diabetic nephropathy are strongly suggested in terms of normalizing the expression of the Prorenin Receptor gene followed by reducing the level of blood Prorenin.
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Prorenin Receptor blockers effects on cardiovascular complications of diabetes and hypertension
Expert Opinion on Investigational Drugs, 2006Co-Authors: Atsuhiro Ichihara, Yuki Kaneshiro, Fumiaki SuzukiAbstract:When the ‘handle region’ of the Prorenin prosegment interacts with the (pro)renin Receptor, the Prorenin molecule partially changes the conformation to an enzymatically active state. On the other hand, the Receptor triggers its own intracellular signalling pathways independent of the renin–angiotensin system (RAS). The ‘handle region’ peptide competitively binds to the Receptor as a decoy peptide and inhibits both the non-proteolytic activation of Prorenin and the RAS-independent intracellular signals. Therefore, Prorenin Receptor blockers including the decoy peptide may have superior benefits on end-organ damage in diabetes and hypertension compared with conventional RAS inhibitors.
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binding properties of rat Prorenin and renin to the recombinant rat renin Prorenin Receptor prepared by a baculovirus expression system
International Journal of Molecular Medicine, 2006Co-Authors: A Nurun H M Nabi, Ayano Kageshima, Tsutomu Nakagawa, M N Uddin, Enoch Y Park, Fumiaki SuzukiAbstract:The rat recombinant renin/Prorenin Receptor (AB188298 in DDJB), which conjugated with FLAG epitope in its N-terminus, was expressed in a baculovirus expression system. The recombinant Receptor, prepared from the cytoplasmic fraction of the insect cells, was identified by Western blotting using anti-FLAG antibody. Prorenin as well as renin bound to the Receptor with different binding affinities. Their K d values were estimated at 8.0 and 20 nM, respectively. The amounts of Prorenin and renin bound to the immobilized Receptors were 1.0 and 0.2 pmole, respectively. The Prorenin bound to the Receptor had renin activity and the renin kept the activity at similar level to that before the binding. The K m of their complexes was the same at 3.3 μM when sheep angiotensinogen was used as the substrate. Their V max values were 5.5 and 10 nM·h -1 , respectively. The molecular activities of Prorenin and renin bound to the Receptor were 1.1 and 10 h -1 , respectively. From these findings, rat Prorenin as well as renin was indicated to bind to the recombinant Receptor and express the enzymatic activity in vitro.
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increased expression of cyclooxygenase 2 in the renal cortex of human Prorenin Receptor gene transgenic rats
Kidney International, 2006Co-Authors: Yuki Kaneshiro, Tsutomu Nakagawa, Fumiaki Suzuki, Atsuhiro Ichihara, Tomoko Takemitsu, Mariyo Sakoda, Matsuhiko Hayashi, Tadashi InagamiAbstract:Increased macula densa cyclooxygenase-2 (COX-2) is observed in diabetic rats and may contribute to hyperfiltration states. However, the signals mediating increased COX-2 expression in diabetic rats remain undetermined. We recently found that non-proteolytic activation of Prorenin by site-specific binding proteins, such as Prorenin Receptor, plays a pivotal role in the development of diabetic nephropathy. The present study was designed to determine the contribution of Prorenin Receptor to renal cortical COX-2 expression. The COX-2 mRNA and protein levels of six 4-week-old male wild-type rats and six human Prorenin Receptor gene-transgenic (hProRenRcTg) rats were measured by real-time polymerase chain reaction methods, Western blotting, and immunohistochemistry, and compared. There were no differences between the two groups in arterial pressure measured by telemetry, urinary sodium excretion, or renal levels of rat Prorenin Receptor mRNA. The renal cortical COX-2 mRNA levels of the hProRenRcTg rats were significantly higher than those of the wild-type rats, and the renal cortical COX-2 protein levels were also higher in hProRenRcTg rats than in the wild-type rats. Immunohistochemical analysis revealed that COX-2 immunostaining was predominantly present in the macula densa cells, and significantly more COX-2-positive cells were present in the hProRenRcTg rats than in the wild-type rats. In addition, COX-2 inhibition with NS398 significantly decreased renal cortical blood flow in the hProRenRcTg rats but not in the wild-type rats. These results strongly suggest that human Prorenin Receptor directly or indirectly contributes to the regulation of renal cortical COX-2 expression.
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Prorenin Receptor blockade inhibits development of glomerulosclerosis in diabetic angiotensin ii type 1a Receptor deficient mice
Journal of The American Society of Nephrology, 2006Co-Authors: Atsuhiro Ichihara, A Nurun H M Nabi, Tsutomu Nakagawa, Fumiaki Suzuki, Yuki Kaneshiro, Tomoko Takemitsu, Mariyo Sakoda, Akira Nishiyama, Takeshi Sugaya, Matsuhiko HayashiAbstract:Blockade of the renin-angiotensin system slows the progression of diabetic nephropathy but fails to abolish the development of end-stage nephropathy of diabetes. The Prorenin-to-active renin ratio significantly increases in diabetes, and Prorenin binding to its Receptor in diabetic animal kidney induces the nephropathy without its conventional proteolytic activation, suggesting that angiotensin II (AngII) may not be the decisive factor causing the nephropathy. For identification of an AngII-independent mechanism, diabetes was induced in wild-type mice and AngII type 1a Receptor gene–deficient mice by streptozotocin treatment, and their development and progression of diabetic nephropathy were assessed. In addition, prolonged inhibition of angiotensin-converting enzyme and prolonged Prorenin Receptor blockade were compared for their efficacy in preventing the nephropathy that occurred in diabetic AngII type 1a Receptor gene–deficient mice. Only the Prorenin Receptor blockade with a short peptide of Prorenin practically abolished the increased mitogen-activated protein kinase (MAPK) activation and nephropathy despite unaltered increase in AngII in diabetic kidney. These results indicate that the MAPK activation signal leads to the diabetic nephropathy but not other renin-angiotensin system–activated mechanisms in the glomeruli. It is not only AngII but also intraglomerular activation of MAPK by the Receptor-associated Prorenin that plays a pivotal role in diabetic nephropathy.
Deborah Stuart - One of the best experts on this subject based on the ideXlab platform.
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abstract 095 mutation in the furin cleavage site of the Prorenin Receptor attenuates angiotensin ii induced hypertension and albuminuria
Hypertension, 2019Co-Authors: Nirupama Ramkumar, Deborah Stuart, Will Wheatley, Donald E KohanAbstract:Cleavage of the extra-cellular domain of the (pro)renin Receptor (PRR) yields a soluble fragment (sPRR) which can promote angiotensin-II (Ang-II) formation. Although alterations in plasma sPRR leve...
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collecting duct principal but not intercalated cell Prorenin Receptor regulates renal sodium and water excretion
American Journal of Physiology-renal Physiology, 2018Co-Authors: Nirupama Ramkumar, Elena Mironova, Deborah Stuart, Nikita Abraham, Yang Gao, Shuping Wang, Jayalakshmi Lakshmipathi, James D StockandAbstract:The collecting duct is the predominant nephron site of Prorenin and Prorenin Receptor (PRR) expression. We previously demonstrated that the collecting duct PRR regulates epithelial Na+ channel (ENa...
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nephron Prorenin Receptor deficiency alters renal medullary endothelin 1 and endothelin Receptor expression
Physiological Research, 2018Co-Authors: Nirupama Ramkumar, Deborah Stuart, Nikita Abraham, Donald E KohanAbstract:The endothelin (ET) and Prorenin/renin/Prorenin Receptor (PRR) systems have opposing physiological effects on collecting duct (CD) salt and water reabsorption. It is unknown if the CD ET and renin/PRR systems interact, hence we examined the effects of deleting CD renin or nephron PRR on CD ET system components. PRR knockout (KO) mice were polyuric and had markedly increased urinary ET-1 and inner medullary CD (IMCD) ET-1 mRNA. PRR KO mice had greatly increased IMCD ETA Receptor mRNA and protein, while ETB mRNA and protein were decreased. Water loaded wild-type mice with similar polyuria as PRR KO mice had modestly increased urinary ET-1 excretion and inner medullary ET-1 mRNA, while inner medullary ETA and ETB mRNA or protein expression were unaffected. In contrast to PRR KO, CD Prorenin/renin KO did not alter ET system components. Taken together, these results suggest that the nephron PRR is involved in regulating CD ET system expression, but this effect may be independent of CD-derived renin.
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renal tubular epithelial cell Prorenin Receptor regulates blood pressure and sodium transport
American Journal of Physiology-renal Physiology, 2016Co-Authors: Nirupama Ramkumar, James D Stockand, Atsuhiro Ichihara, Elena Mironova, Deborah Stuart, Nikita Abraham, Shuping Wang, Vladislav Bugay, Donald E KohanAbstract:The physiological significance of the renal tubular Prorenin Receptor (PRR) has been difficult to elucidate due to developmental abnormalities associated with global or renal-specific PRR knockout (KO). We recently developed an inducible renal tubule-wide PRR KO using the Pax8/LC1 transgenes and demonstrated that disruption of renal tubular PRR at 1 mo of age caused no renal histological abnormalities. Here, we examined the role of renal tubular PRR in blood pressure (BP) regulation and Na(+) excretion and investigated the signaling mechanisms by which PRR regulates Na(+) balance. No detectable differences in BP were observed between control and PRR KO mice fed normal- or low-Na(+) diets. However, compared with controls, PRR KO mice had elevated plasma renin concentration and lower cumulative Na(+) balance with normal- and low-Na(+) intake. PRR KO mice had an attenuated hypertensive response and reduced Na(+) retention following angiotensin II (ANG II) infusion. Furthermore, PRR KO mice had significantly lower epithelial Na(+) channel (ENaC-α) expression. Treatment with mouse Prorenin increased, while PRR antagonism decreased, ENaC activity in isolated split-open collecting ducts (CD). The Prorenin effect was prevented by protein kinase A and Akt inhibition, but unaffected by blockade of AT1, ERK1/2, or p38 MAPK pathways. Taken together, these data indicate that renal tubular PRR, likely via direct Prorenin/renin stimulation of PKA/Akt-dependent pathways, stimulates CD ENaC activity. Absence of renal tubular PRR promotes Na(+) wasting and reduces the hypertensive response to ANG II.
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abstract 021 nephron specific deletion of the Prorenin Receptor modulates blood pressure and urinary na excretion
Hypertension, 2015Co-Authors: Nirupama Ramkumar, James D Stockand, Atsuhiro Ichihara, Elena Mironova, Deborah Stuart, Shuping Wang, Vladislav Bugay, Mykola Mamenko, Oleh Pochynyuk, Donald E KohanAbstract:The nephron Prorenin Receptor (PRR) may modulate blood pressure (BP) and Na+ balance. Since previous models of PRR knockout (KO) mice had early lethality and/or structural defects, we developed an inducible nephron-wide PRR KO using the Pax8/LC1 transgenes. Disruption of nephron PRR at 1 month of age caused no renal histological abnormalities. On a normal Na+ diet, wild-type (WT) and PRR KO mice had similar BP and Na+ excretion. However, PRR KO mice had elevated PRC (KO- 377 ± 77 vs WT- 127 ± 19 ng Ang-I/ml/hr) and a 50% decrease in renal ENaC-α protein. Protein levels of NHE3, NKCC2, NCC and ENaC-β/γ were similar between the two groups. Treatment with mouse Prorenin (10 nM for 30 min) increased ENaC channel number by 2-fold, but not open probability, in isolated split-open cortical collecting ducts (CCD) from WT mice; this was prevented by Akt inhibition (A6730) but unaffected by blockade of AT-1 (losartan), ERK1/2 (U0126) or p38 MAPK (SB203580). Addition of Prorenin (10 nM) did not change isolated CCD [Ca2+]i as assessed by Fura-2 loading (10 min exposure with readings every 3 sec). On a low Na+ diet, PRR KO mice had increased Na+ excretion (Day 2: KO - 66 ± 11 vs WT- 42 ± 6 μmol/day; Day 6: KO - 39 ± 4 vs ET- 23 ± 4 μmol/day) however, no differences in BP were observed. PRC was elevated in PRR KO mice on a low Na+ diet (KO- 384 ± 40 vs WT-174 ± 12 ng/ Ang-I/ml/hr). PRR KO mice had an attenuated hypertensive response to Angiotensin-II (Ang-II) infusion at 600 ng/Kg/min for 2 weeks (MAP: KO - 117 ± 4 vs WT - 133 ± 4 mm Hg over the course of Ang-II infusion). Urinary Na+ excretion was elevated in Ang-II treated PRR KO mice as compared to WT mice (KO-344 ± 14 vs WT-268 ±30 μmol/day). Taken together, these data indicate that nephron PRR, likely via direct Prorenin/renin stimulation of an Akt-dependent pathway, stimulates CCD ENaC activity. Absence of nephron PRR promotes Na+ wasting and reduces the hypertensive response to Ang-II.
