Antiangiogenic Therapy in Diabetic Nephropathy

Zent, Roy; Pozzi, Ambra

doi:10.1681/asn.2005121290

Cited by 10 publications

(6 citation statements)

References 26 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Although diabetic mice exhibited significant weight loss, the extent of body weight reduction was comparable to previous reports utilizing this model [25]. In the diabetic wild-type mice, albuminuria, glomerular hypertrophy, glomerular hyperfiltration (as evidenced by an increased Ccr) and renal hypertrophy were observed, consistent with previous study [37]. These abnormalities were significantly exacerbated in the diabetic VASH1 +/− mice compared with the diabetic wild-type mice, except for the change in the Ccr.…”

Section: Discussionsupporting

confidence: 90%

Exacerbation of Diabetic Renal Alterations in Mice Lacking Vasohibin-1

et al. 2014

View full text Add to dashboard Cite

Vasohibin-1 (VASH1) is a unique endogenous inhibitor of angiogenesis that is induced in endothelial cells by pro-angiogenic factors. We previously reported renoprotective effect of adenoviral delivery of VASH1 in diabetic nephropathy model, and herein investigated the potential protective role of endogenous VASH1 by using VASH1-deficient mice. Streptozotocin-induced type 1 diabetic VASH1 heterozygous knockout mice (VASH1+/−) or wild-type diabetic mice were sacrificed 16 weeks after inducing diabetes. In the diabetic VASH1+/− mice, albuminuria were significantly exacerbated compared with the diabetic wild-type littermates, in association with the dysregulated distribution of glomerular slit diaphragm related proteins, nephrin and ZO-1, glomerular basement membrane thickning and reduction of slit diaphragm density. Glomerular monocyte/macrophage infiltration and glomerular nuclear translocation of phosphorylated NF-κB p65 were significantly exacerbated in the diabetic VASH1+/− mice compared with the diabetic wild-type littermates, accompanied by the augmentation of VEGF-A, M1 macrophage-derived MCP-1 and phosphorylation of IκBα, and the decrease of angiopoietin-1/2 ratio and M2 macrophage-derived Arginase-1. The glomerular CD31+ endothelial area was also increased in the diabetic VASH1+/− mice compared with the diabetic-wild type littermates. Furthermore, the renal and glomerular hypertrophy, glomerular accumulation of mesangial matrix and type IV collagen and activation of renal TGF-β1/Smad3 signaling, a key mediator of renal fibrosis, were exacerbated in the diabetic VASH1+/− mice compared with the diabetic wild-type littermates. In conditionally immortalized mouse podocytes cultured under high glucose condition, transfection of VASH1 small interfering RNA (siRNA) resulted in the reduction of nephrin, angiopoietin-1 and ZO-1, and the augmentation of VEGF-A compared with control siRNA. These results suggest that endogenous VASH1 may regulate the development of diabetic renal alterations, partly via direct effects on podocytes, and thus, a strategy to recover VASH1 might potentially lead to the development of a novel therapeutic approach for diabetic nephropathy.

show abstract

Section: Discussionsupporting

confidence: 90%

Exacerbation of Diabetic Renal Alterations in Mice Lacking Vasohibin-1

et al. 2014

View full text Add to dashboard Cite

show abstract

“…These events are essential for the development of new blood vessels from preexisting ones. This molecule specifically targets endothelial cells and promotes their proliferation, survival, migration, and sprouting (61). On the other hand, an antiangiogenic factor, such as endostatin, inhibits vascular growth by down regulating VEGF (20).…”

Section: Discussionmentioning

confidence: 99%

Increased endogenous H₂S generation by CBS, CSE, and 3MST gene therapy improves ex vivo renovascular relaxation in hyperhomocysteinemia

Sen

Sathnur

Kundu

et al. 2012

American Journal of Physiology-Cell Physiology

102

View full text Add to dashboard Cite

Hydrogen sulfide (H2S) has recently been identified as a regulator of various physiological events, including vasodilation, angiogenesis, antiapoptotic, and cellular signaling. Endogenously, H2S is produced as a metabolite of homocysteine (Hcy) by cystathionine β-synthase (CBS), cystathionine γ-lyase (CSE), and 3-mercaptopyruvate sulfurtransferase (3MST). Although Hcy is recognized as vascular risk factor at an elevated level [hyperhomocysteinemia (HHcy)] and contributes to vascular injury leading to renovascular dysfunction, the exact mechanism is unclear. The goal of the current study was to investigate whether conversion of Hcy to H2S improves renovascular function. Ex vivo renal artery culture with CBS, CSE, and 3MST triple gene therapy generated more H2S in the presence of Hcy, and these arteries were more responsive to endothelial-dependent vasodilation compared with nontransfected arteries treated with high Hcy. Cross section of triple gene-delivered renal arteries immunostaining suggested increased expression of CD31 and VEGF and diminished expression of the antiangiogenic factor endostatin. In vitro endothelial cell culture demonstrated increased mitophagy during high levels of Hcy and was mitigated by triple gene delivery. Also, dephosphorylated Akt and phosphorylated FoxO3 in HHcy were reversed by H2S or triple gene delivery. Upregulated matrix metalloproteinases-13 and downregulated tissue inhibitor of metalloproteinase-1 in HHcy were normalized by overexpression of triple genes. Together, these results suggest that H2S plays a key role in renovasculopathy during HHcy and is mediated through Akt/FoxO3 pathways. We conclude that conversion of Hcy to H2S by CBS, CSE, or 3MST triple gene therapy improves renovascular function in HHcy.

show abstract

“… 92 Also, in the early stages of diabetic nephropathy, glomerular capillary expansion is well described, 88 peri-glomerular angiogenic vessels have been reported, 93 excess VEGF-driven endothelial cell proliferation is observed, 94 and anti-angiogenic therapy has shown some promise in reducing glomerular hypertrophy. 95 Also, therapies directed at increasing blood flow or endothelial cell proliferation and repair in chronic progressive renal fibrosis 89 , 96 have met with some success at preserving the renal microvasculature. Therefore, renal glomerular and peritubular microvascular endothelial cells clearly can respond to angiogenic stimuli, but these mechanisms are inhibited in progressive renal fibrosis ( Figure 2 ).…”

Section: A Failed Angiogenic Response In Ckd?mentioning

confidence: 99%

Tipping the balance from angiogenesis to fibrosis in CKD

Ballermann

Obeidat

2014

Kidney International Supplements

View full text Add to dashboard Cite

Chronic progressive renal fibrosis leads to end-stage renal failure many patients with chronic kidney disease (CKD). Loss of the rich peritubular capillary network is a prominent feature, and seems independent of the specific underlying disease. The mechanisms that contribute to peritubular capillary regression include the loss of glomerular perfusion, as flow-dependent shear forces are required to provide the survival signal for endothelial cells. Also, reduced endothelial cell survival signals from sclerotic glomeruli and atrophic or injured tubule epithelial cells contribute to peritubular capillary regression. In response to direct tubular epithelial cell injury, and the inflammatory reaction that ensues, capillary pericytes dissociate from their blood vessels, also reducing endothelial cell survival. In addition, direct inflammatory injury of capillary endothelial cells, for instance in chronic allograft nephropathy, also contributes to capillary dropout. Chronic tissue hypoxia, which ensues from the rarefaction of the peritubular capillary network, can generate both an angiogenic and a fibrogenic response. However, in CKD, the balance is strongly tipped toward fibrogenesis. Understanding the underlying mechanisms for failed angiogenesis in CKD and harnessing endothelial-specific survival and pro-angiogenic mechanisms for therapy should be our goal if we are to reduce the disease burden from CKD.

show abstract

Antiangiogenic Therapy in Diabetic Nephropathy

Cited by 10 publications

References 26 publications

Exacerbation of Diabetic Renal Alterations in Mice Lacking Vasohibin-1

Exacerbation of Diabetic Renal Alterations in Mice Lacking Vasohibin-1

Increased endogenous H₂S generation by CBS, CSE, and 3MST gene therapy improves ex vivo renovascular relaxation in hyperhomocysteinemia

Tipping the balance from angiogenesis to fibrosis in CKD

Contact Info

Product

Resources

About

Antiangiogenic Therapy in Diabetic Nephropathy

Cited by 10 publications

References 26 publications

Exacerbation of Diabetic Renal Alterations in Mice Lacking Vasohibin-1

Exacerbation of Diabetic Renal Alterations in Mice Lacking Vasohibin-1

Increased endogenous H2S generation by CBS, CSE, and 3MST gene therapy improves ex vivo renovascular relaxation in hyperhomocysteinemia

Tipping the balance from angiogenesis to fibrosis in CKD

Contact Info

Product

Resources

About

Increased endogenous H₂S generation by CBS, CSE, and 3MST gene therapy improves ex vivo renovascular relaxation in hyperhomocysteinemia