LRG1 loss effectively restrains glomerular TGF-β signaling to attenuate DKD in diabetic mice

scRNA-seq analysis 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 demonstrated that LRG1 loss was sufficient to reverse all significant molecular pathway changes in diabetic mouse GECs, which were also associated with the dampening of TGF-β-induced gene expression. Moreover, LRG1 loss also led to a significant attenuation of TGF-β-mediated gene expression in podocytes and mesangial cells of diabetic mice. These results indicate that increased LRG1 directly potentiates TGF-β signaling in glomerular cells in an autocrine and paracrine manner to promote DKD, and indirectly via glomerular cross-talk. 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 of control and diabetic mice.