Anti–TGF-β1 Antibody Therapy in Patients with Diabetic Nephropathy

Voelker, James R.; Berg, Paul H.; Sheetz, Matthew J.; Duffin, Kevin L.; Shen, Tong; Moser, Brian A.; Greene, Tom; Blumenthal, Samuel S.; Rychlík, Ivan; Yagil, Yoram; Zaoui, Philippe; Lewis, Julia B.

doi:10.1681/asn.2015111230

Cited by 224 publications

(160 citation statements)

References 41 publications

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“…Studies from experimental diabetic animals further substantiated the role of TGF-β1 in the pathogenesis of DN [16]. Neutralizing antibodies against TGF-β1 reversed the type II diabetic renal injury [17]. In continuation to the existing studies, here we show that supraphysiological doses of GH induce renal hypertrophy and proteinuria that involves the activation of TGF-β/SMAD pathway.…”

supporting

confidence: 84%

Growth hormone induces mitotic catastrophe of podocytes and contributes to proteinuria

Nishad

Mukhi

et al. 2019

Preprint

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24Growth hormone (GH) had direct effects on the glomerular podocyte. Increased levels of GH 25 are implicated in the pathogenesis of renal abnormalities in acromegaly and in diabetic 26 nephropathy in Type 1 diabetes mellitus. We investigated the role of Transforming growth 27 factor-β1 (TGF-β1) in GH's effects on the glomerular podocyte. Exposure of podocytes to GH 28 resulted in elevated expression of TGF-β1 and was concurrent with increased phosphorylation 29 of SMAD2/3 and nuclear accumulation of SMAD4. Conditioned media from podocytes exposed 30 to GH also triggered SMAD signaling. Podocytes treated with GH showed increased 31 permeability to albumin. Mice injected with GH demonstrated increased kidney size, glomerular 32 hypertrophy, and proteinuria. The renal manifestations in GH injected mice were associated with 33 increased TGF-β1 expression and activation of TGF-β1 signaling pathways. Concurrent 34 administration of TGF-β receptor antagonist (SB431542) with GH abrogated these renal effects 35 of GH administration. These results reveal the role of TGF-β1 in GH's actions on the glomerular 36 podocyte and provide a novel mechanistic basis for GH-induced glomerular dysfunction in 37 clinical conditions such as diabetes and acromegaly. 38 39 40 41 42 43

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supporting

confidence: 84%

Growth hormone induces mitotic catastrophe of podocytes and contributes to proteinuria

Nishad

Mukhi

et al. 2019

Preprint

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“…58,59 Indeed, a recent clinical study of anti-TGF-b1 antibody blockade in patients with DKD failed to show beneficial effects when added to RAS blockade. 60 Although this lack of treatment efficacy could be multifactorial, it further underscores the need for better understanding of TGF-b functions and their downstream signaling pathways in specific kidney cell types for the design of more targeted treatment strategies. Moreover, in contrast to ALK1 or ENG, whose haploinsufficiency is associated with hereditary hemorrhagic telangiectasia, 61 LRG1 deficiency in mice does not appear to result in major physiologic deficits.…”

Section: Discussionmentioning

confidence: 99%

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

Hong

Lü

et al. 2019

JASN

110

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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 receptorlike 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.Diabetic kidney disease (DKD) is a frequent complication of diabetes mellitus (DM) and the most common cause of ESRD in the United States. 1 Intensive glycemic control, BP control, and blockade of the renin-angiotensin-aldosterone system are the gold standard for current treatment of patients with DKD. 2-4 However, these established regimens provide only partial therapeutic effects, 5 indicating that pathogenic mechanisms driving DKD progression may not be targeted by current treatments. In addition, several recent clinical trials in DKD treatments were unsuccessful, 5-8 highlighting an unmet need for better understanding of mechanisms mediating the early stages of DKD for the design of novel preventive therapeutic strategies.Lrg1 expression that colocalize with CD31 outside the tubules. Scale bars, 20 mm. (D) Semiquantitative scoring of Lrg1 mRNA colocalized with Pecam mRNA (n=3 mice per group, 20 gloms scored per mouse). (E) In situ hybridization of LRG1 mRNA (red) combined with CD31 immunofluorescence (green) on human kidney sections with nuclear counterstain. Glomeruli are outlined with dotted lines on upper panels, and magnified view of the box is shown in lower panels. Scale bar, 50 mm. (F) Semiquantitative scoring of LRG1 mRNA colocalized with CD31...

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“…This is particularly relevant in light of the recently published clinical trial, in which blocking TGF-b failed to protect against progression of diabetic nephropathy. 61 (D) Quantification of nuclear b-catenin (normalized to histone H3) is shown. (E) PT cells were incubated with Wnt3a (20 ng/ml) for 24 hours or dilution buffer, and then, levels of Axin2 transcripts were measured by qPCR.…”

Section: Discussionmentioning

confidence: 99%

Blocking TGF-β and β-Catenin Epithelial Crosstalk Exacerbates CKD

Khodo¹,

Neelisetty²,

Phillips³

et al. 2017

JASN

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The TGF- and Wnt/-catenin pathways have important roles in modulating CKD, but how these growth factors affect the epithelial response to CKD is not well studied. TGF- has strong profibrotic effects, but this pleiotropic factor has many different cellular effects depending on the target cell type. To investigate how TGF- signaling in the proximal tubule, a key target and mediator of CKD, alters the response to CKD, we injured mice lacking the TGF- type 2 receptor specifically in this epithelial segment. Compared with littermate controls, mice lacking the proximal tubular TGF- receptor had significantly increased tubular injury and tubulointerstitial fibrosis in two different models of CKD. RNA sequencing indicated that deleting the TGF- receptor in proximal tubule cells modulated many growth factor pathways, but Wnt/-catenin signaling was the pathway most affected. We validated that deleting the proximal tubular TGF- receptor impaired -catenin activity and Genetically restoring-catenin activity in proximal tubules lacking the TGF- receptor dramatically improved the tubular response to CKD in mice. Deleting the TGF- receptor alters many growth factors, and therefore, this ameliorated response may be a direct effect of -catenin activity or an indirect effect of-catenin interacting with other growth factors. In conclusion, blocking TGF- and -catenin crosstalk in proximal tubules exacerbates tubular injury in two models of CKD.

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Anti–TGF-β1 Antibody Therapy in Patients with Diabetic Nephropathy

Cited by 224 publications

References 41 publications

Growth hormone induces mitotic catastrophe of podocytes and contributes to proteinuria

Growth hormone induces mitotic catastrophe of podocytes and contributes to proteinuria

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

Blocking TGF-β and β-Catenin Epithelial Crosstalk Exacerbates CKD

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