(Pro)Renin receptor mediates obesity-induced antinatriuresis and elevated blood pressure via upregulation of the renal epithelial sodium channel.

Syed S Quadri,Nrupama Ramkumar,Donald E Kohan,Silas Culver,Helmy M Siragy,Michael Bader

doi:10.1371/journal.pone.0202419

Abstract

Recent studies have demonstrated that the renal (pro)renin receptor (PRR) regulates expression of the alpha subunit of the epithelial sodium channel (α-ENaC). In this study we hypothesized that the renal PRR mediates high fat diet (HFD)-induced sodium retention and elevated systolic blood pressure (SBP) by enhancing expression of the epithelial sodium channel (α-ENaC). In our study we used a recently developed inducible nephron specific PRR knockout mouse. Mice (n = 6 each group) were allocated to receive regular diet (RD, 12 kcal% fat) or a high-fat diet (HFD, 45 kcal% fat) for 10 weeks. Body weight (BW), SBP, urine volume (UV) and urine sodium (UNaV), as well as renal interstitial Angiotensin II (Ang II), and renal medullary expression of PRR, p-SGK-1, α-ENaC were monitored in RD and HFD mice with or without PRR knockout. At baseline, there were no significant differences in BW, BP, UV or UNaV between different animal groups. At the end of the study, HFD mice had significant increases in SBP, BW, and significant reductions in UV and UNaV. Compared to RD, HFD significantly increased mRNA and protein expression of PRR, α-ENaC, p-SGK-1, and Ang II. Compared to HFD alone, PRR knockout mice on HFD had reduced mRNA and protein expression of PRR, p-SGK-1, and α-ENaC, as well as increased UV, UNaV and significantly reduced SBP. RIF Ang II was significantly increased by HFD and did not change in response to PRR knockout. We conclude that obesity induced sodium retention and elevated SBP are mediated by the PRR-SGK-1- α-ENaC pathway independent of Ang II.

Highlights

Obesity is a national and global epidemic which puts the individual at higher risk for heart disease, stroke, diabetes, and high blood pressure (BP)
Upregulation of ENaC is associated with increased sodium retention contributing to the development of increased BP [12,13] and we recently demonstrated that decreased renal α-ENaC expression increases urinary sodium excretion
There were no significant differences in BP, Body weight (BW) and 24-h food intake at baseline (Fig 1)

Summary

Introduction

Obesity is a national and global epidemic which puts the individual at higher risk for heart disease, stroke, diabetes, and high blood pressure (BP). As much as 75% of essential hypertension is attributable to increased body weight [1] and the fact that reductions in body weight significantly decrease blood pressure supports this causal relationship.[2,3,4] the underlying mechanisms governing the relationship between obesity and the increased sodium retention leading to elevated BP are incompletely understood. While obesity increases the sodium retention in various parts of the nephron,[5] the precise mechanisms regulating these changes have not been fully explained

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