(Pro)renin receptor in the kidney: function and significance

Arthur, Gertrude; Osborn, Jeffrey L.; Yiannikouris, Frédérique

doi:10.1152/ajpregu.00259.2020

Cited by 15 publications

(10 citation statements)

References 63 publications

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“…fPRR is highly expressed in renal tubules, and it has a potential role in renal RAS regulation [ 52 ]. Many studies have shown that fPRR could aggravate tissue damage, such as promoting the development of hypertension, diabetic nephropathy, and proteinuria nephropathy, by activating local RAS in tissues and activating the role of proinflammatory and profibrosis factors [ 34 , 53 – 56 ]. The data in the present study showed that fPRR inhibitors PRO20 and fPRR siRNA could significantly inhibit the AOPP-induced expression levels of AGT, ACE, AT1R, and Ang II in HK-2 cells.…”

Section: Discussionmentioning

confidence: 99%

Advanced Oxidation Protein Product Promotes Oxidative Accentuation in Renal Epithelial Cells via the Soluble (Pro)renin Receptor‐Mediated Intrarenal Renin‐Angiotensin System and Nox4‐H₂O₂ Signaling

Xue

Wang

et al. 2021

Oxidative Medicine and Cellular Longevity

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Full-length (pro)renin receptor (fPRR), a research hotspot of the renin-angiotensin system (RAS), plays a serious role in kidney injury. However, the relationship between fPRR and advanced oxidation protein product (AOPP) remains largely unexplored. This study was aimed at exploring the effect of fPRR, especially its 28 kDa soluble form called soluble PRR (sPRR), in AOPP-induced oxidative stress in HK-2 cells, a renal proximal tubular epithelial cell line. Incubation of HK-2 cells with 100 μg/ml AOPP resulted in significant upregulation of fPRR expression and caused an approximately fourfold increase in medium sPRR secretion. However, unmodified albumin did not demonstrate the same effects under the same concentration. Treatment of HK-2 cells with the site-1 protease (S1P) inhibitor PF429242 (40 μM) or S1P siRNA significantly inhibited AOPP-induced sPRR generation. fPRR decoy inhibitor PRO20 and PF429242 treatment for 24 h remarkably attenuated the AOPP-induced upregulation of RAS components. Furthermore, PF429242 significantly reduced the AOPP-stimulated expression of NADPH oxidase 4 (Nox4) and H2O2 expression. The use of a small recombinant protein, named sPRR-His, reversed these alterations. In conclusion, these results provided the first demonstration of AOPP-promoted activation of sPRR. Increased renal proximal tubule Nox4-derived H2O2 contributed to the aggravation of oxidative stress. Targeting S1P-derived sPRR is a promising intervention strategy for chronic kidney disease.

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Section: Discussionmentioning

confidence: 99%

Advanced Oxidation Protein Product Promotes Oxidative Accentuation in Renal Epithelial Cells via the Soluble (Pro)renin Receptor‐Mediated Intrarenal Renin‐Angiotensin System and Nox4‐H₂O₂ Signaling

Xue

Wang

et al. 2021

Oxidative Medicine and Cellular Longevity

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“…Accordingly, genetic deletion of PRR in the tubular system affected urinary acidification (Trepiccione et al, 2016). Moreover, several studies showed that PRR is expressed in renal collecting ducts and significantly contribute to the urinary concentrating abilities of the kidney, to sodium balance and blood pressure control (comprehensively reviewed in (Arthur et al, 2021)). As mentioned above, low prorenin concentrations observed in tubule-renin KO mice might therefore result in an activation of the circulating active renin in order to compensate for the missing tubular effects of prorenin.…”

Section: Discussionmentioning

confidence: 99%

Prorenin from renal tubules is a major driver of diabetic kidney disease

Federlein

Lehrmann

Tauber

et al. 2022

Preprint

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The renin-angiotensin-system (RAS) plays a critical role in diabetic nephropathy, and inhibitors of the RAS are central components in its therapy. Renin circulates in the blood in its active form but also in the form of its enzymatically inactive precursor prorenin. In humans, the plasma prorenin concentration exceeds that of active renin several times. While the plasma concentration of active renin is unchanged or even reduced in diabetic patients, the prorenin concentration increases significantly and it has been shown that high prorenin levels are associated with diabetic microvascular damage. Why prorenin increases in diabetes while active renin is reduced is unclear. Previous studies suggest that there may be formation of prorenin in the tubular system of diabetic kidneys. To investigate the functional consequences of possible tubular renin formation in diabetes, we generated mice with inducible tubule-specific deletion of the renin gene (tubule-renin KO). Under control conditions, tubule-renin KO had no apparent phenotype and plasma and tissue levels of renin and prorenin were similar to those of mice with intact tubular renin (control mice). In control mice type-1 diabetes (streptozotocin, STZ) for 8 to 12 weeks stimulated tubular renin mRNA and protein expression, especially in distal nephron segments including collecting ducts. This increase in renin synthesis in renal tubules was markedly attenuated or even absent in tubule-renin KO mice. Similar to diabetic patients, plasma prorenin was markedly elevated in diabetic control mice. This stimulation of plasma prorenin was absent in mice with tubule-specific deletion of the renin gene. Moreover, the high prorenin levels in renal tissue, which were observed in diabetic control mice, were markedly reduced in tubule-renin KO. Noteworthy, plasma renin activity was not reduced in tubule-renin KO compared with controls, suggesting that renal tubules of diabetic mice mainly release prorenin. Kidneys of control mice with intact tubular renin showed classical signs of diabetic renal damage, such as albuminuria, mesangial expansion, fibrosis, inflammation and capillary rarefaction. All of these parameters were significantly ameliorated in tubule-renin KO, indicating that tubular renin, most likely in its prorenin form, significantly aggravates renal damage in diabetes. These data provide clear evidence for the first time that the tubular renin system is an additional source for circulating prorenin in diabetes, hereby providing an explanation for the paradox regulation of active renin and prorenin in diabetes. Moreover, the data show that tubular renin markedly contributes to the progression of diabetic nephropathy.

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“…Furthermore, the serum concentration of soluble PRR is a potential biomarker of tissue RAS activity (Fu et al, 2021). Previous studies provided full insights into the distribution and function of PRR in kidney diseases (Chen and Xu, 2020;Wang et al, 2020;Arthur et al, 2021). Accordingly, PRR decoy inhibitor PRO20 attenuated albumin overload-induced nephropathy in rats (Fang et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

Inhibitory effect of (pro)renin receptor decoy inhibitor PRO20 on endoplasmic reticulum stress during cardiac remodeling

et al. 2022

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Background: Ectopic activation of renin-angiotensin-system contributes to cardiovascular and renal diseases. (Pro)renin receptor (PRR) binds to renin and prorenin, participating in the progression of nephrology. However, whether PRR could be considered as a therapeutic target for cardiac remodeling and heart failure remains unknown.Materials and methods: Transverse aortic constriction (TAC) surgery was performed to establish a mouse model of chronic pressure overload-induced cardiac remodeling. Neonatal rat cardiomyocytes (CMs) and cardiac fibroblasts (CFs) were isolated and stimulated by Angiotensin II (Ang II). PRR decoy inhibitor PRO20 was synthesized and used to evaluate its effect on cardiac remodeling.Results: Soluble PRR and PRR were significantly upregulated in TAC-induced cardiac remodeling and Ang II-treated CMs and CFs. Results of In vivo experiments showed that suppression of PRR by PRO20 significantly retarded cardiac remodeling and heart failure indicated by morphological and echocardiographic analyses. In vitro experiments, PRO20 inhibited CM hypertrophy, and also alleviated CF activation, proliferation and extracellular matrix synthesis. Mechanically, PRO20 enhanced intracellular cAMP levels, but not affected cGMP levels in CMs and CFs. Moreover, treatment of PRO20 in CFs markedly attenuated the production of reactive oxygen species and phosphorylation of IRE1 and PERK, two well-identified markers of endoplasmic reticulum (ER) stress. Accordingly, administration of PRO20 reversed ER stressor thapsigargin-induced CM hypertrophy and CF activation/migration.Conclusion: Taken together, these findings suggest that inhibition of PRR by PRO20 attenuates cardiac remodeling through increasing cAMP levels and reducing ER stress in both CMs and CFs.

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(Pro)renin receptor in the kidney: function and significance

Cited by 15 publications

References 63 publications

Advanced Oxidation Protein Product Promotes Oxidative Accentuation in Renal Epithelial Cells via the Soluble (Pro)renin Receptor‐Mediated Intrarenal Renin‐Angiotensin System and Nox4‐H₂O₂ Signaling

Advanced Oxidation Protein Product Promotes Oxidative Accentuation in Renal Epithelial Cells via the Soluble (Pro)renin Receptor‐Mediated Intrarenal Renin‐Angiotensin System and Nox4‐H₂O₂ Signaling

Prorenin from renal tubules is a major driver of diabetic kidney disease

Inhibitory effect of (pro)renin receptor decoy inhibitor PRO20 on endoplasmic reticulum stress during cardiac remodeling

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(Pro)renin receptor in the kidney: function and significance

Cited by 15 publications

References 63 publications

Advanced Oxidation Protein Product Promotes Oxidative Accentuation in Renal Epithelial Cells via the Soluble (Pro)renin Receptor‐Mediated Intrarenal Renin‐Angiotensin System and Nox4‐H2O2 Signaling

Advanced Oxidation Protein Product Promotes Oxidative Accentuation in Renal Epithelial Cells via the Soluble (Pro)renin Receptor‐Mediated Intrarenal Renin‐Angiotensin System and Nox4‐H2O2 Signaling

Prorenin from renal tubules is a major driver of diabetic kidney disease

Inhibitory effect of (pro)renin receptor decoy inhibitor PRO20 on endoplasmic reticulum stress during cardiac remodeling

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Product

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Advanced Oxidation Protein Product Promotes Oxidative Accentuation in Renal Epithelial Cells via the Soluble (Pro)renin Receptor‐Mediated Intrarenal Renin‐Angiotensin System and Nox4‐H₂O₂ Signaling

Advanced Oxidation Protein Product Promotes Oxidative Accentuation in Renal Epithelial Cells via the Soluble (Pro)renin Receptor‐Mediated Intrarenal Renin‐Angiotensin System and Nox4‐H₂O₂ Signaling