Negative correlation of urinary miR-199a-3p level with ameliorating effects of sarpogrelate and cilostazol in hypertensive diabetic nephropathy

The prevalence of chronic kidney disease is increasing globally; however, effective therapeutic options are limited. In this study, we aimed to identify urinary miRNAs reflecting the effect of therapeutic intervention in rats with comorbid hypertension and diabetes. Additionally, the potential beneficial effects of anti-platelet sarpogrelate and cilostazol were investigated. Nephropathy progression in streptozotocin (STZ)-treated spontaneously hypertensive rats (SHRs), including albuminuria, collagen deposition, and histopathological changes, was alleviated by sarpogrelate and antihypertensive agent telmisartan. Global analysis of urinary miRNAs identified that miR-199a-3p was commonly reduced by sarpogrelate and telmisartan treatment. In vitro analysis suggested CD151 as a target gene of miR-199a-3p: miR-199a-3p overexpression repressed CD151 levels and miR-199a-3p interacted with the 3′-untranslated region of the CD151 gene. In addition, we demonstrated that the miR-199a-3p/CD151 axis is associated with the transforming growth factor-β1 (TGF-β1)-induced fibrogenic pathway. TGF-β1 treatment led to miR-199a-3p elevation and CD151 suppression, and miR-199a-3p overexpression or CD151-silencing enhanced TGF-β1-inducible collagen IV and α-smooth muscle actin (α-SMA) levels. In vivo analysis showed that the decrease in CD151 and the increase in collagen IV and α-SMA in the kidney from STZ-treated SHR were restored by sarpogrelate and telmisartan administration. In an additional animal experiment using cilostazol and telmisartan, there was a correlation between urinary miR-199a-3p reduction and the ameliorating effects of cilostazol or combination with telmisartan. Collectively, these results indicate that urinary miR-199a-3p might be utilized as a marker for nephropathy treatment. We also provide evidence of the benefits of antiplatelet sarpogrelate and cilostazol in nephropathy progression.