Role of PPARδ agonist seladelpar in mice with diabetic kidney disease
AIM:This study investigates the protective effect of the selective peroxisome proliferator-activated receptor δ(PPARδ)agonist seladelpar on podocytes in a mouse model of diabetic kidney disease(DKD).METHODS:A DKD mouse model was established using streptozotocin and a high-fat diet.Mice were randomly assigned to three groups:control,DKD with vehicle treatment,and DKD with seladelpar treatment at dosages of 1,5 and 10 mg/kg(6 to 7 mice per group).After four weeks of treatment,mice were euthanized,and various parameters were measured,including urinary albumin,creatinine,blood urea nitrogen,serum triglycerides,and cholesterol using respective kits.Renal tissues were processed for histological examination through HE and PAS staining to assess glomerular pathology.The RNA from glomerular tissues was analyzed via RT-qPCR for podocyte marker(Nphs1,Nphs2,Wt1 and Synpo)expression,and the protein expression was evaluated using Western blot for PPARδ.Immunofluorescence staining of frozen renal cortical sec-tions was conducted to quantify WT1-positive cells and desmin protein levels.Transmission electron microscopy was used to observe glomerular ultrastructural changes.RESULTS:(1)PPARδ protein levels in the glomerular tissue of DKD mice were significantly lower than in controls.(2)Mice treated with 10 mg/kg of seladelpar showed reduced blood glu-cose,triglycerides,and cholesterol levels compared to the diabetic nephropathy group.(3)Both 5 mg/kg and 10 mg/kg se-ladelpar treatment groups exhibited decreased urine albumin/creatinine ratios,along with improvements in glomerular hy-pertrophy and mesangial matrix deposition.Increased mRNA expression levels of Nphs1,Nphs2,Wt1,and Synpo were also observed,alongside an increase in WT1-positive cells and a decrease in desmin expression.Additionally,there was a reduction in podocyte foot process fusion and glomerular basement membrane thickness.(4)RNA sequencing indicated that 5 mg/kg seladelpar treatment modulated PPAR signaling pathway and influenced various metabolic pathways,includ-ing bile acid metabolism,carbon metabolism,glutathione metabolism,glycerophospholipid metabolism,and fatty acid metabolism.CONCLUSION:Seladelpar,a PPARδ agonist,mitigates podocyte injury and reduces proteinuria in DKD mice.Notably,the protective effects of seladelpar are partially independent of its hypolipidemic properties.
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