Abstract
Growing evidence indicates that prorenin receptor (PRR) is upregulated in collecting duct (CD) of diabetic kidney. Prorenin is secreted by the principal CD cells, and is the natural ligand of the PRR. PRR activation stimulates fibrotic factors, including fibronectin, collagen, and transforming growth factor-β (TGF-β) contributing to tubular fibrosis. However, whether high glucose (HG) contributes to this effect is unknown. We tested the hypothesis that HG increases the abundance of PRR at the plasma membrane of the CD cells, thus contributing to the stimulation of downstream fibrotic factors, including TGF-β, collagen I, and fibronectin. We used streptozotocin (STZ) male Sprague–Dawley rats to induce hyperglycemia for 7 days. At the end of the study, STZ-induced rats showed increased prorenin, renin, and angiotensin (Ang) II in the renal inner medulla and urine, along with augmented downstream fibrotic factors TGF-β, collagen I, and fibronectin. STZ rats showed upregulation of PRR in the renal medulla and preferential distribution of PRR on the apical aspect of the CD cells. Cultured CD M-1 cells treated with HG (25 mM for 1 h) showed increased PRR in plasma membrane fractions compared to cells treated with normal glucose (5 mM). Increased apical PRR was accompanied by upregulation of TGF-β, collagen I, and fibronectin, while PRR knockdown prevented these effects. Fluorescence resonance energy transfer experiments in M-1 cells demonstrated augmented prorenin activity during HG conditions. The data indicate HG stimulates profibrotic factors by inducing PRR translocation to the plasma membrane in CD cells, which in perspective, might be a novel mechanism underlying the development of tubulointerstitial fibrosis in diabetes mellitus.
Highlights
Growing evidence indicates that prorenin receptor (PRR) is upregulated in collecting duct (CD) of diabetic kidney
The activation of PRR in mesangial cells, podocytes, and proximal tubule cells have been implicated in the pathogenesis of diabetic nephropathy[8,11,12], the underlying mechanism by which PRR contributes to the development of tubulointerstitial fibrosis in the diabetic kidney remains unclear
To oxidative s tress[19], accumulation of glycosylated p roducts[20], and increased c ytokines[21], High glucose (HG) contributes to the activation of intrarenal RAS22, In type 1 diabetic Sprague–Dawley rats, the principal cells of the CD are the main source of prorenin[3,23,24], it is likely that local PRR activation by prorenin during high glucose (HG) conditions contributes to the development of tubulointerstitial fibrosis
Summary
Growing evidence indicates that prorenin receptor (PRR) is upregulated in collecting duct (CD) of diabetic kidney. To oxidative s tress[19], accumulation of glycosylated p roducts[20], and increased c ytokines[21], High glucose (HG) contributes to the activation of intrarenal RAS22, In type 1 diabetic Sprague–Dawley rats, the principal cells of the CD are the main source of prorenin[3,23,24], it is likely that local PRR activation by prorenin during HG conditions contributes to the development of tubulointerstitial fibrosis. We tested the hypothesis that HG increases the abundance of PRR at the plasma membrane of the CD cells, contributing to the stimulation of downstream fibrotic factors, including TGF-β, collagen I, and fibronectin. High glucose increased PRR protein expression levels in the plasma membrane and cytoplasmic cell fractions, augmented PRR-dependent stimulation of downstream profibrotic factors, and intensified the physical interaction between PRR and prorenin, measured by fluorescence resonance energy transfer (FRET) assay
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
