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LRG1 Promotes Diabetic Kidney Disease Progression by Enhancing TGF-B–Induced Angiogenesis

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LRG1 Promotes Diabetic Kidney Disease Progression by Enhancing TGF-B–Induced Angiogenesis BASIC RESEARCH www.jasn.org LRG1 Promotes Diabetic Kidney Disease Progression by Enhancing TGF-b–Induced Angiogenesis Quan Hong,1,2 Lu Zhang,3,1 Jia Fu,1 Divya A. Verghese,1 Kinsuk Chauhan,1 Girish N. Nadkarni,1 Zhengzhe Li,1 Wenjun Ju,4 Matthias Kretzler ,4 Guang-Yan Cai,2 Xiang-Mei Chen,2 Vivette D. D’Agati,5 Steven G. Coca ,1 Detlef Schlondorff,1 John C. He,1,6 and Kyung Lee1 Due to the number of contributing authors, the affiliations are listed at the end of this article. 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 a-2-glycoprotein 1 (LRG1). LRG1 was previously shown to promote neovascularization in mouse models of ocular disease by potentiating endothelial TGF-b/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. J Am Soc Nephrol 30: 546–562, 2019. doi: https://doi.org/10.1681/ASN.2018060599 Diabetic kidney disease (DKD) is a frequent compli- early stages of DKD for the design of novel preventive cation of diabetes mellitus (DM) and the most com- therapeutic strategies. mon cause of ESRD in the United States.1 Intensive glycemic control, BP control, and blockade of the renin-angiotensin-aldosterone system are the gold Received June 8, 2018. Accepted January 28, 2019. standard for current treatment of patients with Q.H. and L.Z. contributed equally to this work. 2–4 DKD. However, these established regimens pro- Published online ahead of print. Publication date available at 5 vide only partial therapeutic effects, indicating that www.jasn.org. pathogenic mechanisms driving DKD progression Correspondence: Dr. Kyung Lee or Dr. John C. He, Division of may not be targeted by current treatments. In addi- Nephrology, Mount Sinai School of Medicine, One Gustave L. tion, several recent clinical trials in DKD treatments Levy Place, New York, NY 10029. E-mail: [email protected] or were unsuccessful,5–8 highlighting an unmet need for [email protected] better understanding of mechanisms mediating the Copyright © 2019 by the American Society of Nephrology 546 ISSN : 1046-6673/3004-546 J Am Soc Nephrol 30: 546–562, 2019 www.jasn.org BASIC RESEARCH Glomerular neoangiogenesis has long been implicated as Significance Statement contributing to the morphology and pathophysiology of DKD,9–11 and dysregulated expression of various endothelial Although glomerular endothelial dysfunction and neoangiogenesis growth factors are implicated in DKD pathogenesis.12 Vascu- have long been implicated as factors contributing to diabetic kidney lar endothelial growth factor (VEGF) A is thought to contrib- disease (DKD) pathophysiology, the molecular basis of these processes is not well understood. The authors previously found fi 13 ute to the initial hyper ltration and microalbuminuria, such that a proangiogenic gene encoding leucine-rich a-2-glycoprotein 1 that blockade of VEGF signaling by pan-VEGF receptor in- (LRG1) was upregulated in isolated glomerular endothelial cells hibitor ameliorates diabetic albuminuria in mice.14 Imbalance from diabetic mice. In this work, they demonstrate in a diabetic of angiopoietin 1 (Ang-1) and angiopoietin 2 (Ang-2), an- mouse model that LRG1 is a novel angiogenic factor that drives DKD pathogenesis through potentiation of endothelial TGF- other family of vascular growth factors necessary for the nor- b fi /activin receptor-like kinase 1 (ALK1) signaling. They also show mal functioning of the glomerular ltration barrier, is also that plasma LRG1 is associated with renal outcome in a cohort of – implicated in altered permeability in DKD.15 17 In addition patients with type 2 diabetes. These findings indicate that LRG1 to vascular growth factors, several other mechanisms of early has a pivotal role in DKD pathogenesis through TGF-b/ALK1 glomerular endothelial cell (GEC) injury are implicated in signaling and is a risk factor for disease progression. DKD pathogenesis, such as decreased nitric oxide availabil- 18–20 21,22 ity and disturbances in endothelial barrier. These of Bambi significantly worsened diabetic glomerulopathy studies suggest that endothelial dysfunction is among the ear- in relatively DKD-resistant C57BL/6 mice, which was as- liest functional changes in diabetic kidneys. Indeed, a study by sociated with increased ALK1-mediated TGF-b signaling. 23 Weil et al. indicated that GEC injury precedes podocyte foot In an opposite manner to BAMBI, LRG1 was shown to process effacement and microalbuminuria in Pima Indians potentiate the proangiogenic ALK1 pathway by recruit- with type 2 diabetes. ment of TGF-b accessory receptor endoglin (ENG).30 Toassess the molecular changes associated with GEC injury This led us to speculate that the function of LRG1 would fi in early DKD, we recently performed transcriptomic pro ling promote diabetes-induced glomerular angiogenesis via of isolated GECs from streptozotocin (STZ)-induced diabetic ALK1-induced signal transduction in GECs. Therefore, in fi mice with endothelial nitric oxide synthase (eNOS) de - this study, we examined the role of LRG1 in diabetic glo- 24 ciency. Analysis of differentially expressed genes indeed merular injury. indicated that angiogenesis and endothelial proliferation pathways were significantly upregulated in GECs of diabetic mice,24 and that leucine-rich a-2-glycoprotein 1 (LRG1) was METHODS among the top upregulated genes. LRG1 is a secreted glyco- protein belonging to the leucine-rich repeat protein family,25 Study Approval whose expression is increased in plasma and urine of patients All mouse studies were approved by the Institutional Animal with a variety of cancer malignancies and is thought to con- Care and Use Committee at the Icahn School of Medicine at tribute to tumor-growth by promoting angiogenesis.26–29 Mount Sinai (ISMMS) and were performed in accordance with Notably, a recent finding by Wang et al.30 demonstrated that its guidelines. LRG1 mediates the proangiogenic effects through enhance- ment of TGF-b1/ALK1-mediated signaling in murine models Mouse Models of ocular disease. Mice were housed in a specific pathogen-free facility with TGF-b regulates many aspects of endothelial functions in- free access to chow and water and a 12-hour day/night cycle. 2 2 cluding cell proliferation in early diabetic kidneys resulting in Lrg1 / mouse strain in C57BL/6J background was obtained glomerular hypertrophy, but also the induction of apoptosis in from the Knock-Out Mouse Project Repository (#VG10067; microvascular endothelial cells.31 These contrasting actions of www.komp.org). Flk1-H2B-EYFP (EYFP) mice in the C57BL/6J TGF-b on endothelial cells (ECs) are regulated by differential background38 were a generous gift from Dr. Margaret Baron activation of two type 1 receptors: the ubiquitously expressed (ISMMS). Diabetes was induced with intraperitoneal injec- ALK5 and predominantly EC-restricted ALK1 receptors. tions of STZ (Sigma-Aldrich, St. Louis, MO) for five consecu- ALK5 activation induces the Smad2/3 activation to block EC tive days (50 mg/g body wt per day). To accelerate diabetic proliferation, migration, and angiogenesis; in contrast, ALK1 nephropathy, unilateral right nephrectomy was performed, as activation induces the Smad1/5/8 activation to promote described,39 3 weeks before STZ injection. Body weight and EC proliferation, migration, and tube formation, resulting fasting blood glucose levels were monitored biweekly. Diabetes in neoangiogenesis.32–36 However, the role of ALK1 in glomer- was confirmed by fasting blood glucose level .300 mg/dl. The ular angiogenesis has not been fully explored. The importance age- and sex-matched littermates injected with citrate vehicle of the TGF-b–induced ALK1 pathway in driving the DKD served as nondiabetic controls. BP was measured using the pathogenesis was shown in our recent report on BMP noninvasive tail-cuff BP system (Kent Scientific, Torrington, and Activin Membrane-Bound Inhibitor (BAMBI), a TGF-b CT). All mice were euthanized at either 12 or 20 weeks post- pseudoreceptor that represses TGF-b signaling.37 Genetic loss STZ or -vehicle injection. J Am Soc Nephrol 30: 546–562, 2019 LRG1 and Diabetic Kidney Disease Progression 547 BASIC RESEARCH www.jasn.org AB 30 4 P=0.004 P<0.001 non-diabetic P<0.05 diabetic 20 2 expression P<0.001 Lrg1 mRNA (RPKM) 10 0 Lrg1 Median-centered Log2 glomerular 0 -2 Vehicle STZ DBA/2J db/db db/db;eNOS-/- C FVB WT OVE26 Neg control D In situ 4 hybridization P<0.01 3 Probes: CD31 2 LRG1 (Scores 0-4) 1 LRG1/CD31 expression 0 OVE26 FVB-WT E F HLD DKD Neg control In situ P<0.01 hybridization 4 Probe: LRG1 3 2 IF: (Scores 0-4) anti-CD31 1 DAPI LRG1/CD31 expression 0 HLD DKD Figure 1.
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