(Pro)renin receptor is involved in mesangial fibrosis and matrix expansion

Kaori Narumi,Takashi Nakamichi,Emiko Sato,Mariko Miyazaki,Sadayoshi Ito,Takuo Hirose,Tae Yamamoto,Hiroshi Sato

doi:10.1038/s41598-017-18314-w

Abstract

(Pro)renin receptor [(P)RR] is expressed in the kidney and is involved in renal injury. Although (P)RR is activated by indoxyl sulfate (IS) and may be related to renal injury, the details remain unclear. We used mouse mesangial cell line SV40 MES13 to investigate the association of (P)RR with mesangial fibrosis or expansion. Furthermore, we examined the correlation between serum soluble (P)RR [s(P)RR] and various laboratory data including serum IS, a uremic toxin that induces renal fibrosis through (P)RR, and pathological indices in chronic kidney disease and particularly in IgA nephropathy patients. In vitro study using SV40 MES13 cells revealed that (P)RR expression significantly increased in the presence of IS. IS stimulated the fibrotic factors’ expression, which was significantly suppressed by (P)RR knockdown. Moreover, it significantly increased the expression of matrix metalloproteinase 9 and tissue inhibitor of metalloproteinase 1 via the ERK1/2 pathway. In addition, the s(P)RR level significantly correlated with serum IS and mesangial injury markers in our patients. Our results suggest that (P)RR is associated with mesangial fibrosis and matrix expansion through the IS-(P)RR-ERK1/2 pathway. Clinically, s(P)RR may be a biomarker of mesangial fibrosis and matrix expansion.

Highlights

(Pro)renin receptor [(P)RR] was initially identified as a member of the renin angiotensin system (RAS) in 20021
A 39-kDa band corresponding to the full-length (P)RR and a 28-kDa band corresponding to the s(P)RR were detected in SV40 MES13 cells by western blotting (Fig. 1A)
The present study revealed new aspects of (P)RR in the progression of mesangial fibrosis and matrix expansion

Summary

Introduction

(Pro)renin receptor [(P)RR] was initially identified as a member of the renin angiotensin system (RAS) in 20021. Previous studies have revealed that (P)RR blockade improved glomerulosclerosis in human (P)RR-transgenic rats[7] and that the serum levels of s(P)RR correlated with the degree of renal dysfunction in chronic kidney disease (CKD) patients[8] These results suggest that (P)RR is associated with the progress of renal injury. IS promotes cell proliferation and tissue factor expression in vascular smooth muscle cells[13], and induces TGF-β1 and α-smooth muscle actin expression in proximal tubular cells through (P)RR14 Based on these results, we hypothesized that IS accumulated by renal failure activates (P)RR and contributes to mesangial injury, and that (P)RR could be a marker for evaluating pathological change of CKD. We investigated the relationship between (P)RR and IS in CKD patients

Methods

Results

Conclusion