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J Am Soc Nephrol. 2019 Mar 11. pii: ASN.2018060599. doi: 10.1681/ASN.2018060599. [Epub ahead of print]

LRG1 Promotes Diabetic Kidney Disease Progression by Enhancing TGF-β-Induced Angiogenesis.

Author information

1
Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York.
2
Department of Nephrology, State Key Laboratory of Kidney Diseases, National Clinical Research Center of Kidney Diseases, Chinese PLA General Hospital, Chinese PLA Institute of Nephrology, Beijing, China.
3
Department of Nephrology, The First Affiliated Hospital of Xiamen University, Xiamen, China.
4
Division of Nephrology, University of Michigan, Ann Arbor, Michigan.
5
Department of Pathology, Columbia University Medical Center, New York, New York; and.
6
Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York; kim.lee@mssm.edu cijiang.he@mssm.edu.
7
Renal Section, James J. Peters Veterans Affair Medical Center, Bronx, New York.

Abstract

BACKGROUND:

Glomerular endothelial dysfunction and neoangiogenesis have long been implicated in the pathogenesis of diabetic kidney disease (DKD). However, the specific molecular pathways contributing to these processes in the early stages of DKD are not well understood. Our recent transcriptomic profiling of glomerular endothelial cells identified a number of proangiogenic genes that were upregulated in diabetic mice, including leucine-rich α-2-glycoprotein 1 (LRG1). LRG1 was previously shown to promote neovascularization in mouse models of ocular disease by potentiating endothelial TGF-β/activin receptor-like kinase 1 (ALK1) signaling. However, LRG1's role in the kidney, particularly in the setting of DKD, has been unclear.

METHODS:

We analyzed expression of LRG1 mRNA in glomeruli of diabetic kidneys and assessed its localization by RNA in situ hybridization. We examined the effects of genetic ablation of Lrg1 on DKD progression in unilaterally nephrectomized, streptozotocin-induced diabetic mice at 12 and 20 weeks after diabetes induction. We also assessed whether plasma LRG1 was associated with renal outcome in patients with type 2 diabetes.

RESULTS:

LRG1 localized predominantly to glomerular endothelial cells, and its expression was elevated in the diabetic kidneys. LRG1 ablation markedly attenuated diabetes-induced glomerular angiogenesis, podocyte loss, and the development of diabetic glomerulopathy. These improvements were associated with reduced ALK1-Smad1/5/8 activation in glomeruli of diabetic mice. Moreover, increased plasma LRG1 was associated with worse renal outcome in patients with type 2 diabetes.

CONCLUSIONS:

These findings identify LRG1 as a potential novel pathogenic mediator of diabetic glomerular neoangiogenesis and a risk factor in DKD progression.

KEYWORDS:

TGF-beta; diabetic nephropathy; glomerular endothelial cells; proteinuria

PMID:
30858225
DOI:
10.1681/ASN.2018060599

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