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

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.

Inflammation-activated CXCL16 pathway contributes to tubulointerstitial injury in mouse diabetic nephropathy

“…Diabetic dyslipidemia has been shown to be associated with the development of cardiovascular disease and kidney dysfunction [22] . Studies have revealed that dyslipidemia might contribute to the progression of DN via Toll-like receptor 4 signaling, the renin-angiotensin system, transforming growth factor-β signaling, and oxidative stress [23][24][25][26] . Ruan et al proposed that inflammatory stress plays an important role in contributing to ectopic lipid accumulation [15] .…”

MiR-505 suppressed the growth of hepatocellular carcinoma cells via targeting IGF-1R

“…Increasing evidence uncovered that miR-NAs modulated the aerobic glycolysis via targeting the enzymes involved in glycolysis such as GLUT1, G6PD and LDHA [30][31][32][33]. IGF-1R is a transmembrane protein with tyrosine kinase activity belonging to the insulin receptor family [34][35][36]. Up-regulation of IGF-1R has been observed in several cancers, including HCC and renal cell carcinoma [37,38].…”

c-Myc promotes renal fibrosis by inducing integrin αv-mediated transforming growth factor-β signaling

“…The procedures were performed as described previously. 47 Amplification was performed using the following primers: 5 0 -TCATCTTGGCAGTT CTCGCA-3 0 (forward) and 5 0 -TCTTCTTGAGGTGGTCGGAC-3 0 (reverse) for mouse ITGAV, 5 0 -GGCACAAAGACCGTTGA-3 0 (forward) and 5 0 -GCTGAATCCTCCTTGACAAA-3 0 (reverse) for rat ITGAV, 5 0 -CGGACACACAACGTCTTGGAA-3 0 (forward) and 5 0 -AGGATGTA GGCGGTGGCTTTT-3 0 (reverse) for mouse c-Myc, 5 0 -GGGACA GTGTTCTCTGCCTCTGC-3 0 (forward) and 5 0 -AAGTTGCCACCGCC ACCGTCATC-3 0 (reverse) for rat c-Myc, 5 0 -AGGTCGGTGTGAACG GATTTG-3 0 (forward) and 5 0 -TGTAGACCATGTAGTTGAGGTCA-3 0 (reverse) for mouse glyceraldehyde-3-phosphate dehydrogenase, and 5 0 -GACATGCCGCCTGGAGAAAC-3 0 (forward), and 5 0 -AGCCCAG GATGCCCTTTAGT-3 0 (reverse) for rat glyceraldehyde-3-phosphate dehydrogenase.…”

“…Cell proliferation was assessed by the BrdU assay as previously described. 47 Briefly, 10 mmol/l BrdU labeling solution was added to the culture medium, followed by incubation at 37 C for 4 hours. Then cells were fixed, denatured, and incubated with an anti-BrdU-POD (peroxidase) antibody for 90 minutes at room temperature.…”