LRH-1 activation alleviates diabetes-induced podocyte injury by promoting GLS2-mediated glutaminolysis.
LRH-1 activation alleviates diabetes-induced podocyte injury by promoting GLS2-mediated glutaminolysis.
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DOI：
10.1111/cpr.13479
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发表时间：
2023-11
影响因子：
8.5
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中科院分区：
文献类型：
--
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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. Impairment of glutamine degradation and utilization in podocytes under diabetic kidney disease: LRH‐1 positively regulates GlS2‐mediated glutaminolysis, and downregulation of LRH‐1 expression contributes to diabetes‐induced disturbance of energy metabolism and injury in podocytes.
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影响因子：
8
作者：
Miranda, Diego A.;Krause, William C.;Ingraham, Holly A.
通讯作者：
Ingraham, Holly A.
影响因子：
9
作者：
Schwaderer, Juliane;Phan, Truong San;Delgado, M. Eugenia
通讯作者：
Delgado, M. Eugenia
影响因子：
3.7
作者：
Badole SL;Jangam GB;Chaudhari SM;Ghule AE;Zanwar AA
通讯作者：
Zanwar AA
影响因子：
5.8
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Martin Vazquez, Eugenia;Cobo-Vuilleumier, Nadia;Araujo Legido, Raquel;Marin-Canas, Sandra;Nola, Emanuele;Dorronsoro, Akaitz;Lopez Bermudo, Lucia;Crespo, Alejandra;Romero-Zerbo, Silvana Y.;Garcia-Fernandez, Maria;Martin Montalvo, Alejandro;Rojas, Anabel;Comaills, Valentine;Bermudez-Silva, Francisco J.;Gannon, Maureen;Martin, Franz;Eizirik, Decio;Lorenzo, Petra I.;Gauthier, Benoit R.
通讯作者：
Gauthier, Benoit R.
影响因子：
4
作者：
Hewitson TD;Smith ER
通讯作者：
Smith ER