Nephrology Division, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
Nephrology Division, Department of Medicine, Baylor College of Medicine, Houston, Texas, USA.
FASEB J. 2023 Oct;37(10):e23175. doi: 10.1096/fj.202300420R.
Many studies have highlighted the importance of moderate exercise. While it can attenuate diabetic kidney disease, its mechanism has remained unclear. The level of myokine irisin in plasma increases during exercise. We found that irisin was decreased in diabetic patients and was closely related to renal function, proteinuria, and podocyte autophagy injury. Muscle-specific overexpression of PGC-1α (mPGC-1α) in a mouse model is known to increase plasma irisin levels. The mPGC-1α mice were crossed with db/m mice to obtain db/db mPGC-1α+ mice in the present study. Compared to db/db mice without mPGC-1α, plasma irisin was increased, and albuminuria and glomerular pathological damage were both alleviated in db/db mPGC-1α+ mice. Impaired autophagy in podocytes was restored as well. Irisin inhibited the activation of the PI3K/AKT/mTOR signaling pathway in cultured human podocytes and improved damaged autophagy induced by high glucose levels. Then, db/db mice were treated with recombinant irisin, which had similar beneficial effects on the kidney as those in db/db mPGC-1α+ mice, with alleviated glomerular injury and albuminuria. Moreover, the autophagy in podocytes was also significantly restored. These results suggest that irisin secreted by skeletal muscles protects the kidney from diabetes mellitus damage. It also restores autophagy in podocytes by inhibiting the abnormal activation of the PI3K/AKT/mTOR signaling pathway. Thus, irisin may become a new drug for the prevention and treatment of diabetic nephropathy.
许多研究都强调了适度运动的重要性。虽然它可以减轻糖尿病肾病，但具体机制尚不清楚。在运动过程中，血浆中的肌肉因子鸢尾素水平升高。我们发现糖尿病患者的鸢尾素水平降低，且与肾功能、蛋白尿和足细胞自噬损伤密切相关。已知在小鼠模型中肌肉特异性过表达 PGC-1α（mPGC-1α）会增加血浆鸢尾素水平。本研究中将 mPGC-1α 小鼠与 db/m 小鼠杂交，获得 db/db mPGC-1α+小鼠。与没有 mPGC-1α 的 db/db 小鼠相比，db/db mPGC-1α+小鼠的血浆鸢尾素增加，白蛋白尿和肾小球病理损伤均减轻。受损的足细胞自噬也得到了恢复。鸢尾素抑制了培养的人足细胞中 PI3K/AKT/mTOR 信号通路的激活，并改善了高糖水平诱导的受损自噬。然后，db/db 小鼠用重组鸢尾素进行治疗，对肾脏的有益作用与 db/db mPGC-1α+小鼠相似，肾小球损伤和白蛋白尿减轻，并且足细胞中的自噬也明显恢复。这些结果表明，骨骼肌分泌的鸢尾素可保护肾脏免受糖尿病损害。它还通过抑制 PI3K/AKT/mTOR 信号通路的异常激活来恢复足细胞中的自噬。因此，鸢尾素可能成为预防和治疗糖尿病肾病的一种新药。
