Tubulointerstitial fibrosis (TIF) is crucial in the development of renal fibrosis in diabetic nephropathy(DN). Previous data shows that SIRTI plays an important role on fibrosis, but the effect on TIF in DN and underlying mechanisms remains uncertain. In this study, we evaluated the vital role of SIRT1 and identified SIRT1 as a downstream target gene of microRNA-34a-5p (miR-34a-5p) in TIF of DN. The result revealed that expression of miR-34a-5p, fibronectin(FN),collagen type I (COLT) and transforming growth factor beta 1 (TGF-beta 1) were up-regulated accompanied by the corresponding down-regulation of SIRTI in renal tissues of high fat diet and streptozotocin(HFD/STZ)induced diabetic mice with DN, and that the SIRTI mRNA level was negatively correlated with miR-34a-5p expression in high glucose stimulated human proximal tubule cell line(HK-2) cells. We then demonstrated that overexpression of SIRTI reduced, whereas small interfering RNA targeting SIRTI enhanced the expressions of TGF-beta 1 and fibrosis-related genes including FN and COLT in HK-2 cells. Furthermore, we identified that miR-34a-5p directly suppressed SIRTI to increase the profibrogenic effects of TGF-beta 1 through targeting the 3'un-translated region of SIRTI. The functional correlation of miR-34a-5p induced SIRTI decrease was supported by overexpression and inhibition of miR-34a-5p in HK-2 cells. All the results reveal that SIRT1 which is vital in the evolution of renal TIF in DN can be directly suppressed by miR-34a-5p, and suggest that miR-34a-5p is a new target for DN treatment. (C) 2018 Elsevier Inc. All rights reserved.