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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE294491 | GEO | 2025/09/17

REPOSITORIES: GEO

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Project description:Diabetic nephropathy (DN) as a common complication of diabetes is the primary cause of end-stage renal disease. Sodium butyrate (NaB) is a short chain fatty acid in the metabolic products of intestinal bacterium, and its kidney protective effect has been reported in DN. However, its underlying mechanism remains unclear. The aim of the present study was to investigate the effect of NaB on globe transcriptome changes in DN. In our study, eight-week-male db/db mice which were established DN mice were randomly divided into two groups: the DN+NaB group (DN mice treated with NaB, 5g/kg/day) and the DN group (DN mice treated with saline). Also, the normal db/m mice were used as NC group. Further, blood glucose, body weight, urinary microalbumin and urinary creatinine of mice were measured in three groups. Whole-transcriptome analysis was performed by RNA sequencing (RNA-Seq) to evaluate profiling of lncRNAs and messenger RNAs (mRNAs). Bioinformatic analysis was performed to predict the potential NaB-related lncRNAs and genes in DN. The expressions of lncRNAs and mRNAs were tested by quantitative real-time polymerase chain reaction (qRT-PCR) in renal tissues and mesangial cells treated with NaB. The results of the present study demonstrated that NaB ameliorated renal dysfunction in DN mice. Moreover, RNA-Seq results identified that 17 lncRNAs and 180 mRNAs reversely changed in DN+NaB group when compared with those in DN group. Additionally, the integrated co-expression networks of NaB-related lncRNAs revealed these lncRNAs interacted with 155 key mRNAs. The co-expression networks of mRNAs associated to immune response, antigen processing and presentation and acute inflammatory response to antigenic stimulus. The qRT-PCR data showed that eight mRNAs and seven lncRNAs were dysexpressed by NaB in DN mice and mesangial cell under high glucose condition. Furthermore, the co-expression network of inflammation related lncRNAs and mRNAs demonstrated that those 17 reversed lncRNAs and 37 mRNAs also play essential roles in inflammatory response. In summary, the present study suggests that NaB ameliorates diabetes induced renal dysfunction and regulates transcriptome changes in DN. NaB related lncRNA-mRNA may play roles in the protective effect of NaB in DN.

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

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