Temporal renal expression of angiogenic growth factors and their receptors in experimental diabetes

Rizkalla, Bishoy; Forbes, Josephine M.; Cao, Zemin; Boner, G; Cooper, Mark E.

doi:10.1097/00004872-200501000-00026

Cited by 68 publications

(68 citation statements)

References 47 publications

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“…We also assessed ANGPT expression in isolated glomeruli obtained from diabetic patients and living donors. Similar to previous observations in rodents with long-term diabetes duration, [8][9][10] analysis of human glomeruli showed a significant (but modest) imbalance in favor of ANGPT2 in patients with DN compared with control live donor kidney glomeruli; in contrast to our animal model and other studies, 9 Angpt1 did not change. The most likely explanation for this is that our murine experiments examine early stages of diabetic glomerular disease, where angiogenesis is important.…”

Section: Discussionsupporting

confidence: 90%

“…7,8 Several reports have suggested that DN kidneys have altered expression of VEGF-A, Angpt1, and also Angpt2, the natural antagonist of Angpt1. [8][9][10] In diabetic mice, deletion of podocyte Angpt1, 8 or further overexpression of VEGF-A in podocytes, worsens glomerular morphology and enhances proteinuria. 11 Viral delivery of COMPAngpt1 12 or either glomerular transgenic or systemic overexpression of sVEGFR1 ameliorates albuminuria in DN.…”

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confidence: 99%

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Targeted Glomerular Angiopoietin-1 Therapy for Early Diabetic Kidney Disease

Dessapt-Baradez

Woolf

White

et al. 2014

Journal of the American Society of Nephrology

105

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Vascular growth factors play an important role in maintaining the structure and integrity of the glomerular filtration barrier. In healthy adult glomeruli, the proendothelial survival factors vascular endothelial growth factor-A (VEGF-A) and angiopoietin-1 are constitutively expressed in glomerular podocyte epithelia. We demonstrate that this milieu of vascular growth factors is altered in streptozotocin-induced type 1 diabetic mice, with decreased angiopoietin-1 levels, VEGF-A upregulation, decreased soluble VEGF receptor-1 (VEGFR1), and increased VEGFR2 phosphorylation. This was accompanied by marked albuminuria, nephromegaly, hyperfiltration, glomerular ultrastructural alterations, and aberrant angiogenesis. We subsequently hypothesized that restoration of angiopoietin-1 expression within glomeruli might ameliorate manifestations of early diabetic glomerulopathy. Podocyte-specific inducible repletion of angiopoietin-1 in diabetic mice caused a 70% reduction of albuminuria and prevented diabetes-induced glomerular endothelial cell proliferation; hyperfiltration and renal morphology were unchanged. Furthermore, angiopoietin-1 repletion in diabetic mice increased Tie-2 phosphorylation, elevated soluble VEGFR1, and was paralleled by a decrease in VEGFR2 phosphorylation and increased endothelial nitric oxide synthase Ser 1177 phosphorylation. Diabetes-induced nephrin phosphorylation was also reduced in mice with angiopoietin-1 repletion. In conclusion, targeted angiopoietin-1 therapy shows promise as a renoprotective tool in the early stages of diabetic kidney disease.

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Section: Discussionsupporting

confidence: 90%

mentioning

confidence: 99%

Targeted Glomerular Angiopoietin-1 Therapy for Early Diabetic Kidney Disease

Dessapt-Baradez

Woolf

White

et al. 2014

Journal of the American Society of Nephrology

105

View full text Add to dashboard Cite

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“…In contrast, glomerular VEGF immunostaining increased to a similar extent in both female and male diabetic animals. The increase in glomerular VEGF may promote glomerular permeability, which would contribute to the increased proteinuria and angiotensinogen excretion in the female and male diabetic animals (36,42). The extent of collagen staining was higher in the males, but was not different between the control and diabetic groups of either sex.…”

Section: Discussionmentioning

confidence: 93%

Differential regulation of circulating and renal ACE2 and ACE in hypertensive mRen2.Lewis rats with early-onset diabetes

Yamaleyeva¹,

Gilliam-Davis

Almeida³

et al. 2012

American Journal of Physiology-Renal Physiology

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Yamaleyeva LM, Gilliam-Davis S, Almeida I, Brosnihan KB, Lindsey SH, Chappell MC. Differential regulation of circulating and renal ACE2 and ACE in hypertensive mRen2.Lewis rats with early-onset diabetes. Am J Physiol Renal Physiol 302: F1374 -F1384, 2012. First published February 29, 2012 doi:10.1152/ajprenal.00656.2011We examined the impact of early diabetes on the circulating and kidney renin-angiotensin system (RAS) in male and female mRen2.Lewis (mRen2) hypertensive rats. Diabetes (DB) was induced by streptozotocin (STZ; 65 mg/kg) at 11 wk of age for 4 wk without insulin replacement. Systolic blood pressures were not increased in DB males or females compared with controls (CON). Circulating angiotensinconverting enzyme 2 (ACE2) increased ninefold (P Ͻ 0.05) in DB females and threefold (P Ͻ 0.05) in DB males, but circulating ACE and ANG II were higher in the DB groups. Serum C-reactive protein was elevated in DB females but not DB males, and the vascular responses to acetylcholine and estradiol were attenuated in the DB females. Proteinuria, albuminuria, and angiotensinogen excretion increased to a similar extent in both DB females and males. Glomerular VEGF expression also increased to a similar extent in both DB groups. Renal inflammation (CD68 ϩ cells) increased only in DB females although males exhibited greater inflammation that was not different with DB. Cortical ACE2 did not change in DB females but was reduced (30%) in DB males. Renal neprilysin activity (Ͼ75%, P Ͻ 0.05) was markedly reduced in the DB females to that in the DB and CON males. ACE activity was significantly lower in both female (75%, P Ͻ 0.05) and male (50%; P Ͻ 0.05) DB groups, while cortical ANG II and Ang-(1-7) levels were unchanged. In conclusion, female mRen2 rats are not protected from vascular damage, renal inflammation, and kidney injury in early STZ-induced diabetes despite a marked increase in circulating ACE2 and significantly reduced ACE within the kidney.angiotensin; kidney; neprilysin; hypertension; proteinuria ANGIOTENSIN-CONVERTING ENZYME 2 (ACE2), a homolog of ACE, is recognized as an important enzymatic component of the renin-angiotensin system (RAS) that may regulate functional output of this hormonal system (5,7,8,14,28,30,51,50). Although ACE2 was originally characterized for its ability to hydrolyze ANG I to Ang-(1-9), subsequent studies revealed a very high catalytic activity to convert ANG II to Ang-(1-7) (41,44,45,56,58). Indeed, ACE2 inhibition or genetic knockout studies reveal a heightened sensitivity to ANG II-induced increases in blood pressure, as well as an exacerbation of end-organ damage in these experimental models (31,32,46,48,52,60). In contrast to ACE, circulating ACE2 is low to nondetectable in rodents and humans, and tissue sources of the enzyme are more likely to influence the local RAS (12, 40). Diabetic renal injury is generally associated with a reduction in the activity and/or expression of renal tissue ACE2, which may contribute to a deleterious imbalance in the relative expression of ANG I...

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“…For example, VEGF is closely linked to the increased glomerular permeability seen in diabetes, and this appears to be partly mediated by the AT1 receptor subtype [27]. Furthermore, the pro-sclerotic growth factor CTGF has been reported to play a role in renal fibrosis in diabetic Apoe KO mice [28].…”

Section: Discussionmentioning

confidence: 99%

The endothelin receptor antagonist avosentan ameliorates nephropathy and atherosclerosis in diabetic apolipoprotein E knockout mice

Watson

Schumacher

et al. 2009

Diabetologia

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Aims/hypothesis There is convincing evidence that the endothelin system contributes to diabetic nephropathy and cardiovascular disease. This study aimed to assess the effects of the non-peptidergic endothelin receptor A (ETA) antagonist avosentan in a mouse model of accelerated diabetic nephropathy and atherosclerosis in comparison with the ACE inhibitor, quinapril.Methods Apolipoprotein E (Apoe) knockout (KO) mice (n=20 per group, five groups) were randomised to the following groups: non-diabetic controls and streptozotocininduced diabetic animals gavaged daily for 20 weeks with placebo, avosentan (high dose: 30 mg/kg, or low dose: 10 mg/kg) or quinapril (given in drinking water, 30 mg/kg). Results BP was unchanged by avosentan treatment but decreased with quinapril treatment. Diabetes-associated albuminuria was significantly attenuated by high-dose avosentan after 10 and 20 weeks of treatment. Diabetic animals showed a decreased creatinine clearance, which was normalised by avosentan treatment. In diabetic mice, high-dose avosentan treatment significantly attenuated the glomerulosclerosis index, mesangial matrix accumulation, glomerular accumulation of the matrix proteins collagen IV, and renal expression of genes encoding connective tissue growth factor, vascular endothelial growth factor, transforming growth factor β and nuclear factor κB (p65 subunit). Furthermore, high-dose avosentan treatment was also associated with reduced expression of the genes for ETA, ETB and angiotensin receptor 1. The renoprotective effects of avosentan were comparable or superior to those observed with quinapril. High-dose avosentan also significantly attenuated diabetes-associated aortic atherosclerosis in Apoe KO mice and reduced macrophage infiltration and aortic nitrotyrosine expression. Conclusions/interpretation This study demonstrates that ETA blockade with avosentan may provide an alternate therapeutic strategy for the treatment of diabetic micro-and macrovascular complications.

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Temporal renal expression of angiogenic growth factors and their receptors in experimental diabetes

Cited by 68 publications

References 47 publications

Targeted Glomerular Angiopoietin-1 Therapy for Early Diabetic Kidney Disease

Targeted Glomerular Angiopoietin-1 Therapy for Early Diabetic Kidney Disease

Differential regulation of circulating and renal ACE2 and ACE in hypertensive mRen2.Lewis rats with early-onset diabetes

The endothelin receptor antagonist avosentan ameliorates nephropathy and atherosclerosis in diabetic apolipoprotein E knockout mice

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