Abstract: BACKGROUND: Type 2 diabetes mellitus impairs renal function, and studies have shown that exercise interventions can protect the kidneys. Irisin can protect renal function in diabetic nephropathy patients by restoring autophagy through inhibition of the phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) signaling pathway.
OBJECTIVE: To explore whether exercise can restore autophagy and ameliorate renal injury by inhibiting over-activation of the renal PI3K/Akt/mTOR signaling pathway, as well as to analyze the differences in the effects of different modalities of exercise.
METHODS: Six-week-old Sprague-Dawley rats were randomly divided into a blank control group (normal rats) and a diabetic group, and then the diabetic group was randomly divided into a diabetic model group, a moderate-intensity continuous exercise group, and a high-intensity intermittent exercise group after successful modeling using high-fat, high-sugar feeding plus intraperitoneal administration of low-dose 1% streptozotocin (30 mg/kg). The two exercise groups were subjected to 8 weeks of exercise intervention with different exercise intensities. The fasting blood glucose concentration was detected by glucose oxidase method, glycated hemoglobin levels was measured using a kit, serum insulin concentration was detected by Elisa method, and insulin resistance index was calculated. Gene expression of PI3K, AKT, mTOR, Beclin-1, podocin, and nephrin was detected by RT-PCR. Protein expression of mTOR and autophagy marker proteins LC3-1, LC3-2, and Beclin-1 was detected by western blot
RESULTS AND CONCLUSION: Fasting blood glucose and glycosylated hemoglobin levels were highly significantly increased, insulin resistance levels were significantly increased, and insulin levels were significantly decreased in type 2 diabetic rats. Both exercises resulted in highly significant decreases in fasting blood glucose and glycosylated hemoglobin levels, significant decreases in insulin resistance levels and significant increases in insulin levels in type 2 diabetic rats. Insulin levels were significantly higher in the high-intensity intermittent exercise group compared with the moderate-intensity continuous exercise group. The expression of podocin and nephrind genes was significantly reduced in type 2 diabetic rats and two different forms of exercise significantly the gene expression. There was a further trend toward an increase in gene expression of podocyte-associated proteins in the moderate-intensity continuous exercise group compared with the high-intensity intermittent exercise group, but there was no significant difference. The mRNA and protein expression of PI3K, AKT and mTORC1 in kidney tissues of type 2 diabetic rats were significantly increased, and the expression of autophagy marker proteins Beclin-1 and LC3-2 
and LC3-2/LC3-1 were significantly decreased. Both different forms of exercise significantly decreased the mRNA and protein expression of PI3K, AKT, and mTORC1, and significantly increased the autophagy marker proteins Beclin-1, LC3-2, and LC3-2/LC3-1 in renal tissues. Compared with the moderate-intensity continuous exercise group, there was a trend toward further decreases in mRNA expression of PI3K, AKT, and mTORC1 and protein expression of mTOR, and a trend toward further elevation of Beclin-1, LC3-2, and LC3-2/LC3-1 in the high-intensity intermittent exercise group, but only Beclin-1 showed a significant difference between groups. In summary, renal podocyte injury in type 2 diabetes mellitus with suppressed autophagy is closely related to aberrant activation of the PI3K/AKT/mTORC1 signaling pathway. Both moderate-intensity continuous exercise and high-intensity intermittent exercise can protect the diabetic kidney, reduce podocyte damage, and restore renal podocyte autophagy, which may be achieved by inhibiting the excessive activation of the PI3K/AKT/mTOR signaling pathway. High-intensity intermittent exercise shows a trend toward more favorable restoration of autophagy compared with moderate-intensity continuous exercise, but with a slight decrease in podocyte protein expression.

中国组织工程研究杂志出版内容重点：组织构建；骨细胞；软骨细胞；细胞培养；成纤维细胞；血管内皮细胞；骨质疏松；组织工程

Key words: diabetic nephropathy, podocyte, autophagy, high-intensity intermittent exercise, moderate-intensity continuous exercise, PI3K, AKT, mTOR