Reduced Renal Microvascular Reactivity to Angiotensin II in Diabetic Rats

Inman, Sharon R.; Porter, James P.; Fleming, John T.

doi:10.3109/10739689409148269

Cited by 15 publications

(16 citation statements)

References 31 publications

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“…However, the renal vasculature is also highly sensitive to the vasodilator effects of Ang 1-7, particularly at the afferent arteriole (24), and in states associated with activation of the local RAS, leading to an increase in effective renal plasma flow following an infusion of Ang 1-7 in rats (25). We demonstrate for the first time that the circulating ACE2 activity is significantly increased in diabetic mice, potentially contributing to impaired reactivity to Ang II (23). Moreover, suppression of this circulating angiotensinase activity with a selective ACE2 inhibitor was able to prevent diabetes-associated hyperfiltration.…”

Section: Discussionmentioning

confidence: 75%

“…Increased renal blood flow in early diabetes is thought to be due to dilation of resistance arterioles, associated with an impaired reactivity to exogenous Ang II (23). However, the renal vasculature is also highly sensitive to the vasodilator effects of Ang 1-7, particularly at the afferent arteriole (24), and in states associated with activation of the local RAS, leading to an increase in effective renal plasma flow following an infusion of Ang 1-7 in rats (25).…”

Section: Discussionmentioning

confidence: 99%

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ACE2 Deficiency Modifies Renoprotection Afforded by ACE Inhibition in Experimental Diabetes

et al. 2008

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OBJECTIVE-The degradation of angiotensin (Ang) II by ACE2, leading to the formation of Ang 1-7, is an important step in the renin-angiotensin system (RAS) and one that is significantly altered in the diabetic kidney. This study examines the role of ACE2 in early renal changes associated with diabetes and the influence of ACE2 deficiency on ACE inhibitor-mediated renoprotection.RESEARCH DESIGN AND METHODS-Diabetes was induced by streptozotocin in male c57bl6 mice and ACE2 knockout (KO) mice. After 5 weeks of study, animals were randomized to receive the ACE inhibitor perindopril (2 mg ⅐ kg Ϫ1 ⅐ day Ϫ1 ). Wild-type mice were further randomized to receive the selective ACE2 inhibitor MLN-4760 (10 mg ⅐ kg Ϫ1 ⅐ day Ϫ1 ) and followed for an additional 5 weeks. Markers of renal function and injury were then assessed.RESULTS-Induction of diabetes in wild-type mice was associated with a reduction in renal ACE2 expression and decreased Ang 1-7. In diabetic mice receiving MLN-4760 and in ACE2 KO mice, diabetes-associated albuminuria was enhanced, associated with an increase in blood pressure. However, renal hypertrophy and fibrogenesis were reduced in diabetic mice with ACE2 deficiency, and hyperfiltration was attenuated. Diabetic wild-type mice treated with an ACE inhibitor experienced a reduction in albuminuria and blood pressure. These responses were attenuated in both diabetic ACE2 KO mice and diabetic mice receiving MLN-4760. However, other renoprotective and antifibrotic actions of ACE inhibition in diabetes were preserved in ACE2-deficient mice.CONCLUSIONS-The expression of ACE2 is significantly modified by diabetes, which impacts both pathogenesis of kidney disease and responsiveness to RAS blockade. These data indicate that ACE2 is a complex and site-specific modulator of diabetic kidney disease.

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Section: Discussionmentioning

confidence: 75%

Section: Discussionmentioning

confidence: 99%

ACE2 Deficiency Modifies Renoprotection Afforded by ACE Inhibition in Experimental Diabetes

et al. 2008

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“…A second possible explanation for this finding is that hyperfiltering patients may exhibit increased renal AngII receptor density. However, this, too, is unlikely because studies have shown a downregulation in these receptors (34,35). A third possible cause is a reduced tubuloglomerular feedback signal (36).…”

Section: Discussionmentioning

confidence: 99%

Impact of Renin Angiotensin System Modulation on the Hyperfiltration State in Type 1 Diabetes

Sochett

Cherney

Curtis

et al. 2006

Journal of the American Society of Nephrology

120

125

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The initial stages of diabetic nephropathy are characterized by glomerular hyperfiltration and hypertension, processes that have been linked to initiation and progression of renal disease. Renin angiotensin system (RAS) blockade is commonly used to modify the hyperfiltration state and delay progression of renal disease. Despite this therapy, many patients progress to ESRD, suggesting heterogeneity in the response to RAS modulation. The role of the RAS in the hyperfiltration state in adolescents with uncomplicated type 1 diabetes was examined, segregated on the basis of the presence of hyperfiltration. Baseline renal hemodynamic function was characterized in 22 patients. Eleven patients exhibited glomerular hyperfiltration (GFR > 135 ml/min), and in the remaining 11 patients, the GFR was <130 ml/min. Renal hemodynamic function was assessed in response to a graded angiotensin II (AngII) infusion during euglycemic conditions and again after 21 d of angiotensinconverting enzyme (ACE) inhibition with enalapril. AngII infusion under euglycemic conditions resulted in a significant decline in GFR and renal plasma flow in the hyperfiltration group but not in the normofiltration group. After ACE inhibition, GFR fell but did not normalize in the hyperfiltration group; the normofiltration group showed no change. These data show significant differences in renal hemodynamic function between hyperfiltering and normofiltering adolescents with type 1 diabetes at baseline, after AngII infusion and ACE inhibition. The response to ACE inhibition and AngII in hyperfiltering patients suggests that vasodilation may complement RAS activation in causing the hyperfiltration state. The interaction between glomerular vasoconstrictors and vasodilators requires examination in future studies.

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“…Ca 2ϩ influx through VGCCs is also an important component of the afferent arteriolar response to numerous vasoconstrictor agonists (1,20), such that impaired Ca 2ϩ entry through this pathway could contribute to diminished agonist-induced vasoconstriction in IDDM (40)(41)(42). For example, the selective preglomerular defect in norepinephrine responsiveness in our model of IDDM (6) correlates well with the functional localization of VGCCs within the renal microvasculature (1,20), and is consistent with the postulate that a defect in VGCC activity might underlie altered norepinephrine responsiveness in IDDM.…”

Section: Discussionmentioning

confidence: 99%

Functional impairment of renal afferent arteriolar voltage-gated calcium channels in rats with diabetes mellitus.

Carmines¹,

Ohishi²,

Ikenaga³

1996

J. Clin. Invest.

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Experiments were performed to test the hypothesis that diabetes mellitus is associated with impaired afferent arteriolar responsiveness to opening of voltage-gated calcium channels. Diabetes was induced by injection of streptozocin (65 mg/kg, i.v.) and insulin was administered via an osmotic minipump to achieve moderate hyperglycemia. Sham rats received vehicle treatments. 2 wk later, the in vitro bloodperfused juxtamedullary nephron technique was used to al-

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Reduced Renal Microvascular Reactivity to Angiotensin II in Diabetic Rats

Abstract: We conclude that the blunted reactivity of afferent and efferent arterioles to Ang II among diabetic hydronephotic kidneys cannot be fully explained by the influence of renal vascular-derived dilator prostaglandins.

Cited by 15 publications

References 31 publications

ACE2 Deficiency Modifies Renoprotection Afforded by ACE Inhibition in Experimental Diabetes

ACE2 Deficiency Modifies Renoprotection Afforded by ACE Inhibition in Experimental Diabetes

Impact of Renin Angiotensin System Modulation on the Hyperfiltration State in Type 1 Diabetes

Functional impairment of renal afferent arteriolar voltage-gated calcium channels in rats with diabetes mellitus.

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