MAP4K1 Downregulation by Glucagon-Like Peptide 1 (GLP-1) Receptor Agonists Alleviates Podocyte Injury and Inflammation via the cGAS-STING Pathway in Glomerular Diseases

Background: GLP1R agonists, widely known for their role in glycemic control, have also been observed to confer renal protective effects independent of their blood glucose-lowering properties. Despite these benefits, the underlying mechanisms by which GLP1R agonists exert renoprotective effects remain inadequately understood. Methods: Our study aimed to elucidate these mechanisms, focusing on the effects of the GLP1R agonist liraglutide on podocyte function and gene expression. We employed RNA-seq sequencing to analyze gene transcription in podocytes treated with liraglutide. Additionally, we investigated the role of the gene MAP4K1 by generating podocyte-specific MAP4K1 knockout mice and inducing nephropathy with adriamycin (ADR) and lipopolysaccharide (LPS) models. Results: RNA-seq sequencing revealed that liraglutide significantly modulates gene transcription in podocytes, notably causing substantial downregulation of MAP4K1 expression. Data from the Nephroseq database indicated that MAP4K1 is upregulated in focal segmental glomerulosclerosis (FSGS) patients, suggesting its significant role in kidney pathology. In the ADR nephropathy model, liraglutide administration resulted in a marked decrease in MAP4K1 expression in podocytes, correlating with improved kidney functions. Podocyte-specific MAP4K1 knockout mice exhibited significant amelioration of podocyte injury upon ADR-induced nephropathy, associated with suppression of the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway. Additionally, in the LPS model, MAP4K1 knockout mice showed reduced levels of inflammatory cytokines and notable improvements in podocyte integrity and kidney functions. Conclusion: These findings underscore the pivotal role of MAP4K1 in mediating podocyte injury and the inflammatory response in kidney disease. Targeting the MAP4K1-cGAS-STING axis could be a viable strategy for developing new treatments for chronic kidney disease (CKD), highlighting the therapeutic potential of GLP1R agonists in renal protection.