Isoliquiritigenin Entails Blockade of TGF-β1-SMAD Signaling for Retarding High Glucose-Induced Mesangial Matrix Accumulation

Abstract

Diabetic nephropathy characterized as mesangial fibrosis and glomerulosclerosis results in renal failure and end-stage renal diseases. Enhanced expression and secretion of connective tissue growth factor (CTGF) play an important role in the expansion of glomerular mesangial matrix mostly composed of type IV collagen. Isoliquiritigenin can prevent various renal injuries via its anti-inflammatory action. However, the effect of isoliquiritigenin on diabetic nephropathy has never been explored. The present study was to investigate whether nontoxic isoliquiritigenin inhibited high glucose (HG)-induced mesangial fibrosis by retarding formation of type IV collagen as well as CTGF in human mesangial cells (HRMC). Serum starved cells were cultured in media containing 5.5 mM glucose plus 27.5 mM mannitol as an osmotic control or 33 mM glucose for 3 days with and without 1-20 microM isoliquiritigenin. Exposure of cells to HG caused marked increases in collagen secretion and CTGF expression, which was dose-dependently reversed by isoliquiritigenin at the transcriptional levels. Additionally, isoliquiritigenin boosted HG-plummeted type matrix metalloproteinase-1 (MT-1 MMP) expression and dampened HG-elevated tissue inhibitor of MMP-2 (TIMP-2) expression, facilitating the degradation of mesangial matrix. Isoliquiritigenin inhibited HG-upregulated CTGF and TIMP-2 expression via disturbing TGF-beta1 signaling in HRMC, as evidenced by TGF-beta receptor I kinase (TGF-beta RI) inhibitor. HG-activated SMAD2 through autocrine TGF-beta signaling was repealed by > or =10 microM isoliquiritigenin. HG induced SMAD4 expression of HRMC and obliterated antagonistic SMAD7, whereas isoliquiritigenin suppressed induction of TGF-beta RII and TGF-beta RI with blunting their downstream SMAD signaling. The results demonstrate that the bioactive isoliquiritigenin in licorice diminished mesangial matrix accumulation in response to ambient HG through retarding TGF-beta1-SMAD signaling transduction. Therefore, isoliquiritigenin may be a potential therapeutic agent for the prevention and treatment of mesangial fibrosis and glomerulosclerosis leading to diabetic nephropathy due to longstanding diabetes mellitus.

PI3K/Akt pathway mediates high glucose-induced lipogenesis and extracellular matrix accumulation in HKC cells through regulation of SREBP-1 and TGF-β1

“…Many studies have fully confirmed that high glucose is a positive regulator of TGF-b1 expression in various cells such as human mesangial cells (Li et al 2010), mouse embryonic stem cells ) and rat renal proximal tubular cells . LY294002 or shAkt vector both attenuated high glucose-induced enhanced TGF-b1 and FN expression in HKC cells, which revealed the involvement of PI3K/Akt in extracellular matrix accumulation of HKC cells and also determined that high glucosecaused TGF-b1 up-regulation and extracellular matrix protein production could be suppressed by blocking PI3K/Akt activation pathway.…”

Effects of Panax notoginoside on the expression of TGF-β1 and Smad-7 in renal tissues of diabetic rats

“…Therefore, the regulation of TGF-β1/Smad signaling plays a critical role in the development of DN. Agents [14][15][16] targeting enhancement of Smad7 protein expression and then suppression of TGF-β1 signaling transduction may reverse the functional and pathological changes of DN.…”

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“…They found that it reversed the marked increases in collagen secretion and CTGF expression caused by HG. It also boosted HG-plummeted type matrix metalloproteinase-1 (MT-1 MMP) expression and dampened HG-elevated tissue inhibitor of MMP-2 (TIMP-2) expression, facilitating the degradation of mesangial matrix and diminished mesangial matrix accumulation in response to ambient HG through retarding TGF-beta1-SMAD signaling transduction 29 .…”