SND p102 promotes extracellular matrix accumulation and cell proliferation in rat glomerular mesangial cells via the AT1R/ERK/Smad3 pathway

Jin-lan XU1, Xin-xin GAN1, Jun NI1,2, De-cui SHAO1,3, Yang SHEN1, Nai-jun MIAO1, Dan XU1, Li ZHOU1, Wei ZHANG1, Li-min LU1
1 Department of Physiology and Pathophysiology, Shanghai Medical College, Fudan University, Shanghai 200032, China
2 Department of Nephrology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China
3 Cell Electrophysiology Laboratory, Wannan Medical College, Wuhu 241002, China
Correspondence to: Wei ZHANG:, Li-min LU:,
DOI: 10.1038/aps.2017.184
Received: 6 August 2017
Accepted: 14 December 2017
Advance online: 10 May 2018


SND p102 was first described as a transcriptional co-activator, and subsequently determined to be a co-regulator of Pim-1, STAT6 and STAT5. We previously reported that SND p102 expression was increased in high glucose-treated mesangial cells (MCs) and plays a role in the extracellular matrix (ECM) accumulation of MCs by regulating the activation of RAS. In this study, we further examined the roles of SND p102 in diabetic nephropathy (DN)-induced glomerulosclerosis. Rats were injected with STZ (50 mg/kg, ip) to induce diabetes. MCs or isolated glomeruli were cultured in normal glucose (NG, 5.5 mmol/L)- or high glucose (HG, 25 mmol/L)-containing DMEM. We found that SND p102 expression was significantly increased in the diabetic kidneys, as well as in HG-treated isolated glomeruli and MCs. In addition, HG treatment induced significant fibrotic changes in MCs evidenced by enhanced protein expression of TGF-β, fbronectin and collagen IV, and significantly increased the proliferation of MCs. We further revealed that overexpression of SND p102 significantly increased the protein expression of angiotensin II (Ang II) type 1 receptor (AT1R) in MCs by increasing its mRNA levels via directly targeting the AT1R 3’-UTR, which resulted in activation of the ERK/Smad3 signaling and subsequently promoted the up-regulation of fbronectin, collagen IV, and TGF-β in MCs, as well as the cell proliferation. These results demonstrate that SND p102 is a key regulator of AT1R-mediating ECM synthesis and cell proliferation in MCs. Thus, small molecule inhibitors of SND p102 may be a novel therapeutic strategy for DN.
Keywords: diabetic nephropathy; SND p102; isolated glomeruli; mesangial cells; extracellular matrix accumulation; cell proliferation; Ang II type 1 receptor; ERK; Smad3

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