Article

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

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Abstract

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.

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Acknowledgements

This research was financially supported by the National Natural Science Foundation of China (No 81470591 and 81670664 to Li-min LU; No 81400695 to De-cui SHAO). This work was also supported by the Science and Technology Commission of Shanghai Municipality (14DZ2260200, the project of Shanghai Key Laboratory of Kidney and Blood Purification). All authors declare that no conflicts of interest exist.

Author information

Author notes

    • Jin-lan Xu
    •  & Xin-xin Gan

    These authors contributed equally to this work.

Affiliations

  1. Department of Physiology and Pathophysiology, Shanghai Medical College, Fudan University, Shanghai 200032, China

    • Jin-lan Xu
    • , Xin-xin Gan
    • , Jun Ni
    • , De-cui Shao
    • , Yang Shen
    • , Nai-jun Miao
    • , Dan Xu
    • , Li Zhou
    • , Wei Zhang
    •  & Li-min Lu
  2. Department of Nephrology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China

    • Jun Ni
  3. Cell Electrophysiology Laboratory, Wannan Medical College, Wuhu 241002, China

    • De-cui Shao

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Correspondence to Wei Zhang or Li-min Lu.