Irisin ameliorates diabetic kidney disease by restoring autophagy in podocytes

Abstract

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.

Exercise in Diabetic Nephropathy: Protective Effects and Molecular Mechanism

“…However, the mechanism through which exercise-induced irisin activates AMPK in the kidneys remains unclear, and it is speculated that irisin may bind to the αV-integrin receptor on the kidney cells, causing renal AMPK activation somehow. In addition, the study of Lai et al [121] showed that increased irisin in plasma can inhibit the overactivation of the high-glucose-induced PI3K/AKT/mTOR signaling pathway in human podocytes, thereby restoring podocyte autophagy. Therefore, exercise may ameliorate kidney injury by activating the AMPK signaling pathway or inhibiting theAKT signaling pathway through irisin secreted by the skeletal muscles during exercise, which needs to be further investigated (Figure 7).…”

Roles of Mitochondrial Dysfunction in Diabetic Kidney Disease: New Perspectives from Mechanism to Therapy

“…By targeting Bcl-2 with baicalin, apoptosis can be reduced or become a new target [ 62 ]. The activation of PI3K/AKT/mTOR, a recognized autophagy inhibitory pathway, decreases cellular autophagy [ 63 ]. However, podocytes rarely use mTOR for regulation, so new findings have shown that osmotic ion channels (TRPC6) can damage autophagy by activating calpain, as determined in a new study on the relationship between podocyte cytoskeleton and autophagy [ 64 ].…”

Research progress on Alpinia oxyphylla in the treatment of diabetic nephropathy

“…Recent research indicates that the phosphatidylinositol-3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/Akt/mTOR) signaling pathway plays a crucial role in podocytes, primarily by downregulating autophagy ( Yang X et al, 2020 ; Lai et al, 2023 ). Following DN, elevated levels of inflammatory factors and reactive oxygen species (ROS) can activate cell surface receptors, initiating the PI3K activation process.…”