Abstract 630: Differential Renal And Cardiac Effects Of Nox4 In Chronic Angiotensin II-Dependent Hypertension
A role for Nox4 in hypertension remains in question. Both protective and injurious Nox4-dependent renal and cardiovascular effects have been reported. We assessed whether gene-targeted Nox4 deficiency (Nox4-/- mice) could affect development of hypertension, cardiac hypertrophy and renal function in a model of chronic angiotensin II (AngII)-dependent hypertension. We studied mice transgenic for active human renin under the control of the transthyretin promoter (LinA3 mice); these mice develop hypertension over the course of their lifespan. Four genotypes of mice were generated: Wild-type (WT), LinA3, Nox4-/-, and LinA3/Nox4-/-. Nox4-deficiency prevented the development of hypertension (LinA3: 154 vs LinA3/Nox4-/-: 135 mmHg) and cardiac hypertrophy (LinA3: 2.55 vs LinA3/Nox4-/-: 1.73 mg/g) observed in LinA3 mice (P<0.05) and was associated with reduced systemic oxidative stress (Plasma TBARS - LinA3: 2.13 vs LinA3/Nox4-/-: 1.71 mM). Furthermore, cardiac collagen content was decreased in Nox4-/- versus LinA3 mice. While Nox4 deficiency attenuated hypertension in LinA3 mice, it yielded detrimental effects on renal function. Specifically, albumin-to-creatinine ratio was significantly elevated in LinA3/Nox4-/- mice compared with LinA3, Nox4-/- and WT littermates. LinA3 mice showed evidence of mild segmental glomerulosclerosis. LinA3/Nox4-/- mice developed severe renal lesions including increased glomerular tuft to fibrotic area, global glomerulosclerosiswith numerous foci containing perivascular and peritubular monocyte/macrophage cell infiltration. These findings demonstrate that while global Nox4 deletion may be protective for cardiac pathology and hypertension it is conducive to renal injury in a model of chronic AngII-mediated hypertension. Our data indicate tissue-specific effects of Nox4, which may explain divergent renal and cardiac Nox4 actions in Ang II-dependent hypertension.
Author Disclosures: O.H.I. Majane: None. G.E. Callera: None. Y. He: None. T.T. Antunes: None. A. Gutsol: None. A.C. Montezano: None. R.P. Brandes: None. K. Schröder: None. C.R.J. Kennedy: None. R.M. Touyz: None.
- © 2014 by American Heart Association, Inc.