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Abstract
Insulin resistance is a critical process in the initiation and progression of diabetic nephropathy (DN). Alprostadil (Prostaglandin E1, PGE1) had protective effects on renal function. However, it is unknown whether PGE1 inhibited insulin resistance in renal tubule epithelial cells via autophagy, which plays a protective role in DN against insulin resistance. Insulin resistance was induced by palmitic acid (PA) in human HK-2 cells, shown as the decrease of insulin-stimulated AKT phosphorylation, glucose transporter-4 (GLUT4), glucose uptake and enhanced phosphorylation of insulin receptor substrate 1(IRS-1) at site serine 307 (pIRS-1ser307) and downregulated expression of IRS-1. Along with less abundance of p62, autophagy markers LC3B and Beclin-1 significantly increased in HK-2 cells exposed to PA. Such abnormal changes were significantly reversed by PGE1, which mimicked the role of autophagy gene 7 small interfering RNA (ATG7 siRNA). Furthermore, PGE1 promoted the protein expression of autophagy-related fibroblast growth factor-21 (FGF21), which alleviated insulin resistance. Results from western blotting and immunohistochemistry indicated that PGE1 remarkably restored autophagy, insulin resistance and the FGF21 expression in rat kidney of type 2 diabetes mellitus (T2DM). Collectively, we demonstrated the potential protection of PGE1 on insulin resistance in renal tubules via autophagy-dependent FGF21 pathway in preventing the progression of DN.
Highlights
Autophagy is a major catabolic pathway by which mammalian cells degrade macromolecules and organelles to maintain intracellular homeostasis[6]
The present study for the first time demonstrated that renal tubule epithelial cells were novel insulin-sensitive cells and renal tubular insulin resistance is critical in the pathogenesis of diabetic nephropathy (DN)
The inhibition of insulin resistance by PGE1 resulted from the inactivation on autophagy, which was associated with recovery of type 2 diabetes mellitus (T2DM)-induced renal dysfunction
Summary
Autophagy is a major catabolic pathway by which mammalian cells degrade macromolecules and organelles to maintain intracellular homeostasis[6]. The presence or activation of autophagy plays a protective role in DN against insulin resistance, excessive autophagy results in various renal tubular injury[7]. It has been not reported that PGE1 has the potential protection on insulin resistance in renal tubule epithelial cells via autophagy. Our results indicated that PGE1 inhibited insulin resistance and thereby improved renal dysfunction in T2DM rats. We demonstrated that this decrease of autophagy and consequent upregulation of downstream molecular fibroblast growth factor-21 (FGF21) resulted in the recovery of insulin resistance by PGE1. These studies revealed a potential mechanism for the beneficial action of PGE1 in diabetic renal complication
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