Increased expression of (pro)renin receptor does not cause hypertension or cardiac and renal fibrosis in mice

Rosendahl, Alva; Niemann, Gianina; Lange, Adam; Ahadzadeh, Erfan; Krebs, Christian; Contrepas, Aurélie; Goor, Harry van; Wiech, Thorsten; Bäder, Michael; Schwake, Michael; Peters, Judith C.; Stahl, Rolf A.K.; Nguyen, Geneviève; Wenzel, Ulrich

doi:10.1038/labinvest.2014.83

Cited by 32 publications

(33 citation statements)

References 30 publications

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“…Because prorenin is mostly secreted by CD cells and that the affinity of the receptor for renin and prorenin are in the nanomolar range we performed the following experiments in doses of 10 −8 mol/L prorenin. Next, we tested the ROS suppression efficiency of the scavenger p‐coumaric acid (PCA), which efficiently prevents lipid peroxidation and cytoplasmic ROS formation . Previous treatment with PCA abolishes the prorenin‐induced ROS formation in M‐1 cells.…”

Section: Resultsmentioning

confidence: 99%

“…Next, we tested the ROS suppression efficiency of the scavenger p-coumaric acid (PCA), which efficiently prevents lipid peroxidation and cytoplasmic ROS formation. 29,30 Previous treatment with PCA abolishes the prorenin-induced ROS formation in M-1 cells. Positive controls performed with 200 mmol/L H 2 O 2 greatly increases ROS formation ( Figure 2C).…”

Section: Antioxidants Prevented the Prorenin-induced Ros Formation mentioning

confidence: 99%

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(Pro)renin receptor activation increases profibrotic markers and fibroblast‐like phenotype through MAPK‐dependent ROS formation in mouse renal collecting duct cells

González

Zamora

Reyes-Martínez

et al. 2017

Clin Exp Pharma Physio

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Recent studies suggested that activation of the PRR upregulates profibrotic markers through reactive oxygen species (ROS) formation; however, the exact mechanisms have not been investigated in CD cells. We hypothesized that activation of the PRR increases the expression of profibrotic markers through MAPK-dependent ROS formation in CD cells. Mouse renal CD cell line (M-1) was treated with recombinant prorenin plus ROS or MAPK inhibitors and PRR-shRNA to evaluate their effect on the expression of profibrotic markers. PRR immunostaining revealed plasma membrane and intracellular localization. Recombinant prorenin increases ROS formation (6.0 ± 0.5 vs. 3.9 ± 0.1 nM DCF/μg total protein, P<0.05) and expression of profibrotic markers CTGF (149 ± 12%, P<0.05), α-SMA (160 ± 20%, P<0.05), and PAI-I (153 ± 13%, P<0.05) at 10-8 M. Recombinant prorenin induced phospho ERK 1/2 (p44 and p42) at 10-8 and 10-6 M after 20 min. Prorenin-dependent ROS formation and augmentation of profibrotic factors were blunted by ROS scavengers (trolox, p-coumaric acid, ascorbic acid), the MEK inhibitor PD98059 and PRR transfections with PRR-shRNA. No effects were observed in the presence of antioxidants alone. Prorenin-induced upregulation of collagen I and fibronectin was blunted by ROS scavenging or MEK inhibition independently. PRR-shRNA partially prevented this induction. After 24 h prorenin treatment M-1 cells undergo to epithelial mesenchymal transition phenotype, however MEK inhibitor PD98059 and PRR knockdown prevented this effect. These results suggest that PRR might have a significant role in tubular damage during conditions of high prorenin-renin secretion in the CD.

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Section: Resultsmentioning

confidence: 99%

Section: Antioxidants Prevented the Prorenin-induced Ros Formation mentioning

confidence: 99%

(Pro)renin receptor activation increases profibrotic markers and fibroblast‐like phenotype through MAPK‐dependent ROS formation in mouse renal collecting duct cells

González

Zamora

Reyes-Martínez

et al. 2017

Clin Exp Pharma Physio

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“…Both renal PRR and plasma sPRR were shown to be increased during the development of hypertension 14, 16–18 . BP was increased in transgenic rats with human PRR overexpression in vascular smooth muscle cells 19 , but not with ubiquitous overexpression of PRR 20 . Knockdown of endogenous PRR in the supraoptic nucleus 21 , brain 22 , and neuron 23 , as well as intracerebroventricular infusion of the PRR antagonist PRO20 (the first 20 amino acid residues of the prorenin prosegment, L 1 PTRTATFERIPLKKMPSVR 20 ) 24 , attenuated the development of hypertension.…”

Section: Introductionmentioning

confidence: 90%

Activation of Renal (Pro)Renin Receptor Contributes to High Fructose-Induced Salt Sensitivity

et al. 2017

Hypertension

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A high-fructose (HF) diet is shown to induce salt-sensitive hypertension but the underlying mechanism largely remains unknown. The major goal of the present study was to test the role of renal (pro)renin receptor (PRR) in this model. In Sprague-Dawley rats, HF intake increased renal expression of full-length PRR (fPRR), which were attenuated by allopurinol. HF intake also upregulated renal mRNA and protein expression of sodium/hydrogen exchanger 3 (NHE3) and Na/K/2Cl cotransporter (NKCC2) as well as in vivo NKCC2 activity, all of which were nearly completely blocked by a PRR decoy inhibitor PRO20 or allopurinol treatment. Parallel changes were observed for indices of intrarenal renin-angiotensin-system (RAS) including renal and urinary renin and angiotensin II levels. Radiotelemetry demonstrated that HF or a high-salt diet alone did not affect mean arterial pressure (MAP), but the combination of the two maneuvers induced a ~10 mm Hg increase of MAP, which was blunted by PRO20 or allopurinol treatment. In cultured human kidney 2 cells, both fructose and uric acid (UA) increased protein expression of soluble PRR (sPRR) in a time- and dose-dependent manner; fructose-induced PRR upregulation was inhibited by allopurinol. Taken together, our data suggest that fructose via UA stimulates renal expression of PRR/sPRR that stimulate NHE3 and NKCC2 expression and intrarenal RAS to induce salt-sensitive hypertension.

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“…Systolic blood pressure was measured with a computerized tail-cuff system (Process Control Blood Pressure 2900 series, TSE Systems, Bad Homburg, Germany), as previously described (16,18,22). Mice were placed into metabolic cages for a 6-h urine collection.…”

Section: Methodsmentioning

confidence: 99%

The complement receptor C5aR1 contributes to renal damage but protects the heart in angiotensin II-induced hypertension

Weiß

Rosendahl

Czesla

et al. 2016

American Journal of Physiology-Renal Physiology

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Adaptive and innate immune responses contribute to hypertension and hypertensive end-organ damage. Here, we determined the role of anaphylatoxin C5a, a major inflammatory effector of the innate immune system that is generated in response to complement activation, in hypertensive end-organ damage. For this purpose, we assessed the phenotype of C5a receptor 1 (C5aR1)-deficient mice in ANG II-induced renal and cardiac injury. Expression of C5aR1 on infiltrating and resident renal as well as cardiac cells was determined using a green fluorescent protein (GFP)-C5aR1 reporter knockin mouse. Flow cytometric analysis of leukocytes isolated from the kidney of GFP-C5aR1 reporter mice showed that 28% of CD45-positive cells expressed C5aR1. Dendritic cells were identified as the major C5aR1-expressing population (88.5%) followed by macrophages and neutrophils. Using confocal microscopy, we detected C5aR1 in the kidney mainly on infiltrating cells. In the heart, only infiltrating cells stained C5aR1 positive. To evaluate the role of C5aR1 deficiency in hypertensive injury, an aggravated model of hypertension was used. Unilateral nephrectomy was performed followed by infusion of ANG II (1.5 ng·g(-1)·min(-1)) and salt in wild-type (n = 34) and C5aR1-deficient mice (n = 32). C5aR1-deficient mice exhibited less renal injury, as evidenced by significantly reduced albuminuria. In contrast, cardiac injury was accelerated with significantly increased cardiac fibrosis and heart weight in C5aR1-deficient mice after ANG II infusion. No effect was found on blood pressure. In summary, the C5a:C5aR1 axis drives end-organ damage in the kidney but protects from the development of cardiac fibrosis and hypertrophy in experimental ANG II-induced hypertension.

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Increased expression of (pro)renin receptor does not cause hypertension or cardiac and renal fibrosis in mice

Cited by 32 publications

References 30 publications

(Pro)renin receptor activation increases profibrotic markers and fibroblast‐like phenotype through MAPK‐dependent ROS formation in mouse renal collecting duct cells

(Pro)renin receptor activation increases profibrotic markers and fibroblast‐like phenotype through MAPK‐dependent ROS formation in mouse renal collecting duct cells

Activation of Renal (Pro)Renin Receptor Contributes to High Fructose-Induced Salt Sensitivity

The complement receptor C5aR1 contributes to renal damage but protects the heart in angiotensin II-induced hypertension

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