Growth hormone releasing hormone analogue protects against diabetic renal injury via inhibiting oxidative stress and ferroptosis

MR409 is a synthetic growth hormone-releasing hormone (GHRH) analogue. MR409 has been shown to enhance the survival rate and efficacy of islet cell transplantation in streptozotocin (STZ)-induced diabetes mice and exerts beneficial effects on cardiovascular diseases. The present study investigated the protective effects of MR409 on DB/DB and STZ-induced diabetic mice and to explore the underlying mechanisms that related to oxidative and ferroptosis. DB/DB mice or STZ combined with high fat diet were used to establish the T2D models. MR409 (15 μg/mouse/day) was subcutaneously administrated for 8 weeks. Treatment with MR409 significantly improved renal function and decreased the renal injury and fibrosis in DB/DB mice and STZ-induced mice. MR409 increased the expression of renal GHRH receptor without affecting the growth hormone level. MR409 attenuated oxidative stress, as indicating by decreasing the expressions of NADPH oxidase subunits p22phox, gp91phox, DHE oxidative fluorescence intensity, MDA and 4-HNE expression in the kidney of DB/DB mice. Meanwhile, MR409 inhibited ferroptosis in DB/DB mice, as indicated by upregulating the expressions of GPX4, Nrf2, FTH and downregulating TFR expression. Treatment with MR409 also increased the level of GSH in the kidney of DB/DB mice. Notably, MR409 activated the PPARγ and its downstream targeted gene Klotho in the kidney of the DB/DB mice. Therefore, the present study demonstrated that MR409 alleviates diabetic nephropathy (DN) via attenuating oxidative stress and ferroptosis, which provides a novel insight into the treatment for DN.