Site-1 Protease-Derived Soluble (Pro)Renin Receptor Contributes to Angiotensin II–Induced Hypertension in Mice

Abstract

Activation of PRR ([pro]renin receptor) contributes to enhancement of intrarenal RAS and renal medullary α-ENaC and thus elevated blood pressure during Ang II (angiotensin II) infusion. The goal of the present study was to test whether such action of PRR was mediated by sPRR (soluble PRR), generated by S1P (site-1 protease), a newly identified PRR cleavage protease. F1 B6129SF1/J mice were infused for 6 days with control or Ang II at 300 ng/kg per day alone or in combination with S1P inhibitor PF-429242 (PF), and blood pressure was monitored by radiotelemetry. S1P inhibition significantly attenuated Ang II–induced hypertension accompanied with suppressed urinary and renal medullary renin levels and expression of renal medullary but not renal cortical α-ENaC expression. The effects of S1P inhibition were all reversed by supplement with histidine-tagged sPRR termed as sPRR-His. Ussing chamber technique was performed to determine amiloride-sensitive short-circuit current, an index of ENaC activity in confluent mouse cortical collecting duct cell line cells exposed for 24 hours to Ang II, Ang II + PF, or Ang II + PF + sPRR-His. Ang II–induced ENaC activity was blocked by PF, which was reversed by sPRR-His. Together, these results support that S1P-derived sPRR mediates Ang II–induced hypertension through enhancement of intrarenal renin level and activation of ENaC.

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

“…sPRR is hypothesized to bind to specific ligands and receptors and mediate many signal transduction pathways [ 22 – 30 ]. For example, S1P-derived sPRR through the activation of intrarenal RAS and ENaC mediated Ang II-induced hypertension [ 26 ]. It targeted vasopressin receptor 2 to enhance urine-concentrating capability [ 29 ].…”

The Soluble (Pro)Renin Receptor in Health and Diseases: Foe or Friend?

“…These results suggest that enhanced sPRR may contribute to AngII-induced hypertension via the activation of the local tissue RAS. In support of this notion, S1P inhibition blocking sPRR generation significantly inhibited Ang II-induced hypertension in F1 B6129SF1/J mice, accompanied by decreased renal medullary and urinary renin levels and renal medulla α-ENaC expression, both of which were reversed by sPRR-His infusion (Feng Y et al, 2021). Consistently, loss of endogenous sPRR in mice by mutating the cleavage site of the PRR caused a decreased blood pressure at baseline and attenuated AngII-induced hypertension, which was partially reversed by exogenous recombinant sPRR infusion (Ramkumar N et al, 2021).…”

“…Consistently, loss of endogenous sPRR in mice by mutating the cleavage site of the PRR caused a decreased blood pressure at baseline and attenuated AngII-induced hypertension, which was partially reversed by exogenous recombinant sPRR infusion (Ramkumar N et al, 2021). Of note, endogenous sPRR deficiency induced by either S1P inhibition or the mutation of the cleavage site resulted in elevated fPRR protein levels, which was negatively correlated with blood pressure (BP) in AngII-infused mice (Feng Y et al, 2021;Ramkumar N et al, 2021), indicating that PRR via sPRR but not fPRR contributes to the hypertensive response to AngII infusion. However, these were confused by the observations that PRR inhibition by PRO20 without affecting sPRR generation attenuated AngII-induced hypertension (Wang F et al, 2015), thus we should clarify whether PRO20 blocks sPRR activity or not.…”

Cardiovascular aspects of the (pro)renin receptor: Function and significance

“…157,161 Recently, several reports have demonstrated the relevance of sPRR in the pathogenesis of hypertension. Mice with the treatment of S1P inhibitor PF429242 162 and mutations of the cleavage site of PRR 115,116 exhibited lower BP in response to AngII infusion (300 ng•kg −1 •min −1 for 14 days, 116,162 400 ng•kg −1 •day −1 for 14 days 115 ), accompanied by attenuated AngII-induced vasoconstriction and acetylcholine as well as the activation of intrarenal RAS and ENaC, both of all were partially reversed by F I G U R E 3 Hypertensive actions of the brain (A) and renal (B) (Pro)renin receptor (PRR) in response to multiple stimulus (e.g., Prorenin infusion, AngII infusion, DOCA/salt treatment, Fructose/salt intake, etc.). ACE, angiotensin-converting enzyme; AGT, angiotensinogen; AngI, angiotensin I; AngII, angiotensin II; AT1R, type 1 AngII receptor; ENaC, epithelial sodium channel; Nedd4-2, neural precursor cell expressed by developmentally downregulated gene 4-2; NOX 4 , NADPH oxidase 4; pERK1/2, phosphorylated extracellular signal-regulated kinase 1/2; ROS, reactive oxygen species; SGK-1, serum-and-glucocorticoid-inducible kinase 1 exogenous mouse recombinant sPRR infusion.…”