Sitagliptin ameliorates diabetic nephropathy by blocking TGF-β1/Smad signaling pathway

Abstract

Diabetic nephropathy (DN) is the leading cause of end-stage failure of the kidney, but the efficacy of current strategies available for the prevention of DN remains unsatisfactory. The purpose of this study was to assess whether sitagliptin (SIT) has therapeutic potential for prevention of DN and to investigate its possible mechanism. The effects of SIT on DN were investigated in rats with type 2 diabetes mellitus (T2DM) and rat mesangial cells (MCs) induced by high glucose. T2DM rats were administered at a dose of 10 mg/kg SIT. The kidney index, 24 h urinary protein, blood urea nitrogen (BUN), serum creatinine (Cr), accumulation of glycogen and collagens were investigated by different methods. MCs were administered with SIT at doses of 0.1, 1 and 10 µmol/ml. The possible mechanism of SIT on protection of diabetic kidney injury was examined by expression of transforming growth factor-β1 (TGF-β1)/Smad pathway. The results showed that the SIT-treated diabetic rats significantly reduced diabetic kidney injury by inhibiting the kidney index and attenuating 24 h urinary protein, reducing BUN and serum creatinine, inhibiting progressive renal fibrosis and increassing extracellular matrix including collagen IV and fibronectin. Further studies showed that inhibition of renal fibrosis in SIT-treated diabetic rats and MCs were associated with rebalancing of TGF-β1/Smad pathway. Sitagliptin may be a potent agent for preventing the progression of DN through inhabiting TGF-β1/Smad-mediated renal fibrosis.

Single cell sequencing identifies serine proteases as regulators of myofibroblast differentiation

“…As to the anti-fibrotic action of sitagliptin, we have no mechanism to offer yet. Although DPP4 inhibition has previously been demonstrated to directly inhibit canonical TGFβ signaling via Smad2 in renal fibrosis 60 and TGFβ-mediated myoFB-differentiation by interfering with ERKsignaling 61 , we were not able to confirm these mechanisms in skin FBs. Possible explanations for alternative the anti-fibrotic action of sitagliptin could be interactions with CXCL12/SDF1 (Stromal derived factor 1), a substrate of DPP4 62 which was found to promote scar formation 63 , or with components of the ECM, such as fibronectin , which have been shown to bind latent TGFβ 19 , or DPP4 induced cleavage of growth factors or receptors 62 .…”

Protective Effects of Chromium Picolinate Against Diabetic-Induced Renal Dysfunction and Renal Fibrosis in Streptozotocin-Induced Diabetic Rats

“…The TGF-β1/Smads signaling pathway plays an important role in DN pathogenesis, which includes podocyte injury, basement membrane thickening, mesangial cell proliferation, renal cell apoptosis, and epithelial cell interstitial transformation, among others [32,33]. Studies have confirmed that abnormal activation of the TGF-β1/Smad signaling pathway may be the main cause of renal fibrosis in diabetic nephropathy patients [34].…”

Renoprotective effect of vildagliptin following hepatic ischemia/reperfusion injury

“…Previous studies suggested that the Smad family could act as signal integrators among inflammatory or fibrogenic pathways mediating tissue inflammation [29,30]. On the other hand, a pleiotropic cytokine TGF-b was considered as the main mediator in the development of different pathological disorders including fibrosis, angiogenesis, immunosuppression, post-trauma repair, and inflammation and its effect was mediated by the Smad 2 and Smad 3 signaling molecules [31][32][33].…”

“…On the other hand, a pleiotropic cytokine TGF-b was considered as the main mediator in the development of different pathological disorders including fibrosis, angiogenesis, immunosuppression, post-trauma repair, and inflammation and its effect was mediated by the Smad 2 and Smad 3 signaling molecules [31][32][33]. These molecules were activated in different animal models of renal diseases as obstructive kidney diseases, nephrectomy and diabetic nephropathy [29,30,34].…”