LRH-1 activation alleviates diabetes-induced podocyte injury by promoting GLS2-mediated glutaminolysis.
Jijia HuZongwei ZhangHongtu HuKeju YangZijing ZhuQian YangWei LiangPublished in: Cell proliferation (2023)
Alteration of metabolic phenotype in podocytes directly contributes to the development of albuminuria and renal injury in conditions of diabetic kidney disease (DKD). This study aimed to identify and evaluate liver receptor homologue-1 (LRH-1) as a possible therapeutic target that alleviates glutamine (Gln) metabolism disorders and mitigates podocyte injury in DKD. Metabolomic and transcriptomic analyses were performed to characterize amino acid metabolism changes in the glomeruli of diabetic mice. Next, Western blotting, immunohistochemistry assays, and immunofluorescence staining were used to detect the expression of different genes in vitro and in vivo. Furthermore, Gln and glutamate (Glu) content as well as ATP generation were examined. A decrease in LRH-1 and glutaminase 2 (GLS2) expression was detected in diabetic podocytes. Conversely, the administration of LRH-1 agonist (DLPC) upregulated the expression of GLS2 and promoted glutaminolysis, with an improvement in mitochondrial dysfunction and less apoptosis in podocytes compared to those in vehicle-treated db/db mice. Our study indicates the essential role of LRH-1 in governing the Gln metabolism of podocytes, targeting LRH-1 could restore podocytes from diabetes-induced disturbed glutaminolysis in mitochondria.
Keyphrases
- high glucose
- endothelial cells
- type diabetes
- diabetic nephropathy
- poor prognosis
- binding protein
- amino acid
- cardiovascular disease
- metabolic syndrome
- glycemic control
- south africa
- endoplasmic reticulum stress
- oxidative stress
- adipose tissue
- radiation therapy
- genome wide
- gene expression
- insulin resistance
- pi k akt
- dna methylation
- skeletal muscle
- cell proliferation
- high fat diet induced
- wild type