Loss of LRG1 Effectively Curbs Diabetes-Induced TGF-β Signaling in Glomerular Endothelial and Mesangial Cells to Attenuate Diabetic Kidney Disease (DKD)
- Diabetic Kidney Disease: Basic - I
November 03, 2023 | Location: Exhibit Hall, Pennsylvania Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Diabetic Kidney Disease
- 701 Diabetic Kidney Disease: Basic
- Fu, Jia, Icahn School of Medicine at Mount Sinai, New York, New York, United States
- Sun, Zeguo, Icahn School of Medicine at Mount Sinai, New York, New York, United States
- Feng, Ye, Icahn School of Medicine at Mount Sinai, New York, New York, United States
- Zhang, Weijia, Icahn School of Medicine at Mount Sinai, New York, New York, United States
- He, John Cijiang, Icahn School of Medicine at Mount Sinai, New York, New York, United States
- Lee, Kyung, Icahn School of Medicine at Mount Sinai, New York, New York, United States
Despite the immense burden of DKD, optimal therapies remain limited. Although TGF-β is a well-established central mediator of DKD pathogenesis, because of its pleiotropic actions in multiple organ systems, its indiscriminate blockade is not desirable. Moreover, evidence of diverse kidney cell-specific effects of TGF-β, both deleterious and protective, continues to emerge. TGF-β signaling is strongly influenced by cell type- and context-dependent regulators and determinants, and we previously showed that cell surface modulators, such as LRG1 and BAMBI, can significantly influence TGF-β signaling in kidney disease. Since LRG1 is increased in glomerular ECs in DKD, we posited that LRG1 loss may shift the balance away from excessive pathological endothelial TGF-β signaling to attenuate DKD, without a full systemic blockade of TGF-β signaling associated with unwanted side effects.
Type 1 diabetic OVE26 mice were crossed with Lrg1-/- mice to generate OVE26;Lrg1-/- mice, and DKD progression was assessed by renal function and histopathologic parameters. scRNA-seq was employed for kidney single-cell gene expression analysis of control and diabetic mice.
scRNA-seq confirmed that increased LRG1 is limited to GECs in early diabetic kidneys. As anticipated, LRG1 loss significantly attenuated diabetic glomerulopathy including podocyte loss, and improved renal function. scRNA-seq analysis showed that LRG1 loss was sufficient to reverse all significant molecular pathway changes in GECs in early DKD, which were associated with the dampening of TGF-β-induced gene expression. Notably, LRG1 loss also led to a significant attenuation of TGF-β-mediated gene expression in mesangial cells of diabetic mice. These results indicate that LRG1 promotes DKD by enhancing TGF-β signaling in GECs and mesangial cells in an autocrine and paracrine manner, and indirectly via glomerular cross-talk.
Our study indicates that increased LRG1 directly enhances TGF-β signaling not only in GECs but also in mesangial cells in DKD, thereby exacerbating subsequent podocyte loss. LRG1 loss, while having no gross defects in mice, significantly attenuated diabetic glomerulopathy in OVE26 mice. Therefore, specific antagonisms of LRG1 may be an effective approach to curb TGF-β signaling in glomerular cells and attenuate DKD.
- NIDDK Support