Inhibition of insulin resistance by PGE1 via autophagy-dependent FGF21 pathway in diabetic nephropathy

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.

Prostaglandin E1 Inhibited Diabetes-Induced Phenotypic Switching of Vascular Smooth Muscle Cells Through Activating Autophagy

“…Therefore, our Here, we found that PGE1 mimicked the role of rapamycin on the phenotypic switching and was dramatically counteracted by 3-methyladenine. Our previous study demonstrated that inhibiting autophagy was responsible for the enhancement of FGF21 by PGE1 in palmitic acid-treated HK-2 cells [9]. The current study further demonstrated that autophagy was a new pharmacological target.…”

“…PGE1 also had a significant role in glucose and lipid metabolism in patients with T2DM. Our recent study showed that PGE1 could protect renal function via autophagy in diabetic nephropathy [9]. However, it has not been reported whether PGE1 has the potential protection on the phenotype in VSMCs via autophagy pathway.…”

“…Western blot analysis was performed as described previously [9]. Briefly, 30μg of total proteins from VSMCs were separated by 10% or 15% sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) at 80 V for 30 min and then 120V for 1 h. The protein was transferred to polyvinylidene fluoride membranes (PDVF membrane, Bio-Rad) at 200mA for 1 h. After washing, the membranes were probed with the primary antibodies of α-SMA, vimentin, Collagen I, PCNA, LC3B, Beclin1, p62, mTOR, p-mTOR, AKT, p-AKT, GAPDH (1:1000, Abways, China) overnight at 4°C, followed by Goat Anti-Rabbit IgG (1:5000, Abways, China) for 1.5 h. The blot was detected by chemiluminescent systems with LumiGlo and Peroxide (1:1, Tanon).…”

The tripartite interaction of phosphate, autophagy, and αKlotho in health maintenance

“…The decreased plasma Pi and increased urinary Pi excretion in mice after adminstration of TB-11, the active and functional peptide of beclin 1 futher proves the concept that high autophagy in the kidney promotes negative Pi balance. The restored body growth and reduced mortality in BK/BK;kl/kl mice was abolished by high-Pi diet further The role of autophagy in regulation of renal transport 66,67 including water, 68,69 glucose, 70 cysteine, 71 and other electrolytes 72 have been reported. The current manuscript provides new data linking autophagy with phosphate transport in the renal tubules.…”

Improvement of cardiac dysfunction by L-arginine combined with vitamin C through restoring angiogenesis associated with NADPH/NOS/NO signal pathway in diabetic rats

“…The HE staining was performed as described previously [48]. Brie y, hearts were removed from the rats and xed with 4% paraformaldehyde overnight, and then embedded in para n. The prepared sections were sliced to 8 µm thick and stained with hematoxylin and eosin (HE).…”