(Pro)renin receptor contributes to regulation of renal epithelial sodium channel

Abstract

Recent studies reported increased (Pro)renin receptor (PRR) expression during low-salt intake. We hypothesized that PRR plays a role in regulation of renal epithelial sodium channel (ENaC) through serum and glucocorticoid-inducible kinase isoform 1 (SGK-1)-neural precursor cell expressed, developmentally downregulated 4–2 (Nedd4–2) signaling pathway. Male Sprague–Dawley rats on normal-sodium diet and mouse renal inner medullary collecting duct cells treated with NaCl at 130 mmol/l (normal salt), or 63 mmol/l (low salt) were studied. PRR and α-ENaC expressions were evaluated 1 week after right uninephrectomy and left renal interstitial administration of 5% dextrose, scramble shRNA, or PRR shRNA (n = 6 each treatment). In-vivo PRR shRNA significantly reduced expressions of PRR throughout the kidney and α-ENaC subunits in the renal medulla. In inner medullary collecting duct cells, low salt or angiopoietin II (Ang II) augmented the mRNA and protein expressions of PRR (P < 0.05), SGK-1 (P < 0.05), and α-ENaC (P < 0.05). Low salt or Ang II increased the phosphorylation of Nedd4–2. In cells treated with low salt or Ang II, PRR siRNA significantly downregulated the mRNA and protein expressions of PRR (P < 0.05), SGK-1 (P < 0.05), and α-ENaC expression (P < 0.05). We conclude that PRR contributes to the regulation of α-ENaC via SGK-1-Nedd4–2 signaling pathway.

Unraveling the Physiology of (Pro)Renin Receptor in the Distal Nephron

“…Moreover, the other ENaC subunits (β & γ) remain unchanged. In agreement with our results, Quadri et al showed that in vivo delivery of shRNA against PRR to the kidney of Sprague-Dawley rats selectively reduced α-ENaC expression in the renal medulla but not in the cortex despite the gene knockdown in the whole kidney 33 . These results suggest that PRR may primarily target renal medullary (or inner medullary) ENaC to regulate Na + balance and BP.…”

“…Besides the above-mentioned in vitro data, strong in vivo data from 3 independent studies all support an important role of PRR in ENaC regulation under basal and/or pathophysiological conditions 29, 32, 33 . To our surprise, PRR regulation of ENaC appears to occur only in the renal medulla but not the cortex.…”

“…Moreover, the prorenin effect was similarly unaffected by AT1 blockade 32 . Besides the ENaC regulation at activity level, PRR also upregulates α-ENaC mRNA expression in mIMCD3 cells exposed to low salt media or AngII through serine/threonine-protein kinase-1 and phosphorylated Nedd4-2 {also known as Nedd4L (neural precursor cell-expressed developmentally downregulated gene 4-like)} 33 . Together, the in vitro results suggest that PRR can modulate ENaC expression and activity through distinct mechanisms.…”

(Pro)renin Receptor Is an Amplifier of Wnt/β-Catenin Signaling in Kidney Injury and Fibrosis

“…17 Recent studies also demonstrate that PRR in renal tubular epithelia regulates BP and sodium transport. 18,19 Taken together, these investigations establish a critical role for PRR in regulating normal kidney development, tissue hemostasis, and BP regulation.…”

The critical role of the central nervous system (pro)renin receptor in regulating systemic blood pressure

“…In the kidney, the PRR is mainly expressed in cells of the collecting ducts and in the distal nephron (Advani, et al, 2009), where it may complex with vacuolar H + -ATPase to regulate proton transport (Advani, et al, 2009; Daryadel, et al, 2016). Expression of the PRR is regulated by changes in sodium concentration induced by the cGMP-dependent protein kinase (PKG) pathway in the kidney (Huang & Siragy, 2011; Quadri & Siragy, 2016; Rong, et al, 2015). In addition, PRR expression levels are regulated by Ang II through CREB (cAMP response element binding protein) in the central nervous system (CNS) during hypertension (W.…”