Chaihuang-Yishen Granule Inhibits Diabetic Kidney Disease in Rats through Blocking TGF-β/Smad3 Signaling

Abstract

ObjectiveIncreasing evidence shows that TGF-β1 is a key mediator in diabetic nephropathy (DN) and induces renal fibrosis positively by Smad3 but negatively by Smad7. However, treatment of DN by blocking the TGF-β/Smad pathway remains limited. The present study investigated the anti-fibrotic effect of a traditional Chinese medicine, Chaihuang-Yishen granule (CHYS), on DN.Research Design and MethodsProtective role of CHYS in DN was examined in an accelerated type 1 DN induced by streptozotocin in uninephrectomized Wistar rats. CHYS, at a dose of 0.56 g/kg body weight, was administered by a daily gastric gavage for 20 weeks and the therapeutic effect and potential mechanisms of CHYS on diabetic kidney injury were examined.ResultsTreatment with CHYS attenuated diabetic kidney injury by significantly inhibiting 24-h proteinuria and progressive renal fibrosis including glomerulosclerotic index, tubulointerstitial fibrosis index, and upregulation of extracellular matrix (collagen I, IV, and fibronectin), despite the same levels of blood glucose. Further studies revealed that inhibition of renal fibrosis in CHYS-treated diabetic rats was associated with inhibition of TGF-β1/Smad3 signaling as demonstrated by upregulation of Smad7 but downregulation of TGF-β1, TGF-β receptors, activation of Smad3, and expression of miRNA-21.ConclusionsCHYS may be a therapeutic agent for DN. CHYS attenuates DN by blocking TGF-β/Smad3-mediated renal fibrosis.

Silymarin ameliorates diabetic cardiomyopathy via inhibiting TGF‐β1/Smad signaling

“…In the present study, we found that silymarin downregulated blood glucose level and significantly improved cardiac dysfunction in STZ-induced diabetic rats. When the TGF-b1 receptor is activated, Smad7 dissociates from the TGF-b1 receptor, and Smad2 and Smad3 are activated and phosphorylated (Zhou et al, 2012;Zhao et al, 2014;Xin et al, 2015). In the present study, the level of TGF-b1 was upregulated in DCM, which is consistent with previous studies; however, silymarin administration reduced the level of TGF-b1.…”

Danshen injection ameliorates STZ-induced diabetic nephropathy in association with suppression of oxidative stress, pro-inflammatory factors and fibrosis

“…TGF-β1, a key fibrogenic cytokine, mediates glomerulosclerosis and tubulointerstitial fibrosis in DN by enhancing ECM synthesis. The production of key ECM molecules such as collagen and fibronectin was stimulated by TGF-β1/Smad pathway [23]. Therefore, inhibition of TGF-β1 was reported to significantly decrease the high glucose-induced increase in ECM protein expression [39].…”

“…TGF-β1 has been found to contribute to the pathogenesis of renal fibrosis by increasing production of collagen and fibronectin in DN [23]. It has also been reported that TGF-β1 increases the expression of some ECM proteins via phosphorylated Smad2/3, leading to fibrosis in renal tissue in diabetic model [11,23].…”

“…It has also been reported that TGF-β1 increases the expression of some ECM proteins via phosphorylated Smad2/3, leading to fibrosis in renal tissue in diabetic model [11,23]. Therefore, the expressions of phosphorylated Smad2/3 and TGF-β1 were examined to further investigate the mechanism of Danshen-induced fibrosis suppression.…”

Effects of astragalosides from Radix Astragali on high glucose-induced proliferation and extracellular matrix accumulation in glomerular mesangial cells

“…Therefore, reversing changes in FN and colIV synthesis might play a key role in delaying the progression of DN. TGF-β is a potent fibrogenic factor (23,24). TGF-β 1 is highly expressed in the kidneys of diabetic animals (25) and humans (26) and contributes to the accumulation of ECM.…”