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  3. Insulin deficiency induces rat renal mesangial cell dysfunction via activation of IGF-1/IGF-1R pathway

Insulin deficiency induces rat renal mesangial cell dysfunction via activation of IGF-1/IGF-1R pathway

  • Acta Pharmacol Sin. 2016 Feb;37(2):217-27. doi: 10.1038/aps.2015.128.
Ya-li Kong 1,  Yang Shen 1,  Jun Ni 1,  De-cui Shao 1,  Nai-jun Miao 1,  Jin-lan Xu 1,  Li Zhou 1,  Hong Xue 1,  Wei Zhang 1,  Xiao-xia Wang 2,  Li-min Lu 1
Affiliations

Affiliations

  • 1 Department of Physiology and Pathophysiology, Shanghai Medical College, Fudan University, Shanghai 200032, China.
  • 2 Department of Nephrology, Shanghai Jiao Tong University, School of Medicine, Shanghai 200025, China.
PMID: 26775660 DOI: 10.1038/aps.2015.128
Abstract

Aim: Diabetic nephropathy is one of the major complications of diabetes and the major cause of end-stage renal disease. In this study we investigated the Insulin deficiency (ID) induced changes in renal mesangial cells (MCs) and in the kidney of STZ-induced diabetic rats.

Methods: Cultured rat renal MCs were incubated in ID media. Cell proliferation was analyzed using BrdU incorporation assay. The expression of Insulin Receptor (IR), insulin-like growth factor-1 receptor (IGF-1R), phosphorylated IGF-1R, fibronectin, and collagen IV was determined with Western blot analysis. STZ-induced diabetic rats were treated with an IGF-1R antagonist picropodophyllin (PPP, 20 mg·kg(-1)·d(-1), po) for 8 weeks. After the rats were euthanized, plasma and kidneys were collected. IGF-1 levels in renal cortex were measured with RT-PCR or ELISA. The morphological changes in the kidneys were also examined.

Results: Incubation in ID media significantly increased cell proliferation, the synthesis of fibronectin and collagen IV, and the expression of IGF-1 and IGF-1R and phosphorylated IGF-1R in renal MCs. Pretreatment of the cells with PPP (50 nmol/L) blocked ID-induced increases in cell proliferation and the synthesis of fibronectin and collagen IV; knockdown of IGF-1R showed a similar effect as PPP did. In contrast, treatment of the cells with IGF-1 (50 ng/mL) exacerbated ID-induced increases in cell proliferation. In the kidneys of diabetic rats, the expression of IGF-1, IGF-1R and phosphorylated IGF-1R were significantly elevated. Treatment of diabetic rats with PPP did not lower the blood glucose levels, but significantly suppressed the expression of TGF-β, fibronectin and collagen IV in the kidneys, the plasma levels of urinary nitrogen and creatinine, and the urinary protein excretion.

Conclusion: Insulin deficiency increases the expression of IGF-1 and IGF-1R in renal MCs and the kidney of diabetic rats, which contributes to the development of diabetic nephropathy.

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