LRG1 loss effectively restrains glomerular TGF-β signaling to attenuate diabetic kidney disease.

Autor:	Wang X; Department of Medicine, Division of Nephrology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Nephrology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China., Sun Z; Department of Medicine, Division of Nephrology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA., Fu J; Department of Medicine, Division of Nephrology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA., Fang Z; Department of Medicine, Division of Nephrology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA., Zhang W; Department of Medicine, Division of Nephrology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA., He JC; Department of Medicine, Division of Nephrology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Renal Section, James J. Peters Veterans Affair Medical Center, Bronx, NY 10468, USA. Electronic address: cijiang.he@mssm.edu., Lee K; Department of Medicine, Division of Nephrology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Electronic address: kim.lee@mssm.edu.
Jazyk:	angličtina
Zdroj:	Molecular therapy : the journal of the American Society of Gene Therapy [Mol Ther] 2024 Sep 04; Vol. 32 (9), pp. 3177-3193. Date of Electronic Publication: 2024 Jun 22.
DOI:	10.1016/j.ymthe.2024.06.027
Abstrakt:	Transforming growth factor (TGF)-β signaling is a well-established pathogenic mediator of diabetic kidney disease (DKD). However, owing to its pleiotropic actions, its systemic blockade is not therapeutically optimal. The expression of TGF-β signaling regulators can substantially influence TGF-β's effects in a cell- or context-specific manner. Among these, leucine-rich α2-glycoprotein 1 (LRG1) is significantly increased in glomerular endothelial cells (GECs) in DKD. As LRG1 is a secreted molecule that can exert autocrine and paracrine effects, we examined the effects of LRG1 loss in kidney cells in diabetic OVE26 mice by single-cell transcriptomic analysis. Gene expression analysis confirmed a predominant expression of Lrg1 in GECs, which further increased in diabetic kidneys. Loss of Lrg1 led to the reversal of angiogenic and TGF-β-induced gene expression in GECs, which were associated with DKD attenuation. Notably, Lrg1 loss also mitigated the increased TGF-β-mediated gene expression in both podocytes and mesangial cells in diabetic mice, indicating that GEC-derived LRG1 potentiates TGF-β signaling in glomerular cells in an autocrine and paracrine manner. Indeed, a significant reduction in phospho-Smad proteins was observed in the glomerular cells of OVE26 mice with LRG1 loss. These results indicate that specific antagonisms of LRG1 may be an effective approach to curb the hyperactive glomerular TGF-β signaling to attenuate DKD. Competing Interests: Declaration of interests The authors declare no competing interests. (Copyright © 2024 The American Society of Gene and Cell Therapy. All rights reserved.)
Databáze:	MEDLINE
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