Insulin deficiency induces rat renal mesangial cell dysfunction via activation of
IGF-1/IGF-1R pathway
#MMPMID26775660
Kong YL
; Shen Y
; Ni J
; Shao DC
; Miao NJ
; Xu JL
; Zhou L
; Xue H
; Zhang W
; Wang XX
; Lu LM
Acta Pharmacol Sin
2016[Feb]; 37
(2
): 217-27
PMID26775660
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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-?, 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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