Heme oxygenase activity as a determinant of the renal hemodynamic response to low-dose ANG II

Abstract

II causes renal injury through hemodynamic and other effects, and pressor doses of ANG II induce heme oxygenase-1 (HO-1) as a protective response. The present studies examined the hemodynamic effects of more clinically relevant, lower doses of ANG II and the role of HO activity in influencing these effects. Under euvolemic conditions, ANG II increased arterial pressure and renal vascular resistance. ANG II did not induce oxidative stress, inflammation/injury-related gene expression, or proteinuria and did not alter extrarenal vascular reactivity. At these doses, ANG II failed to increase HO-1 or HO-2 mRNA expression or HO activity. Inhibiting HO activity in ANG II-treated rats by tin mesoporphyrin further increased renal vascular resistances, decreased renal blood flow, and blunted the rise in arterial pressure without inducing oxidative stress or altering expression of selected vasoactive/ injury/inflammation-related genes; tin mesoporphyrin did not alter vasorelaxation of mesenteric resistor vessels. We conclude that in this model renal vasoconstriction occurs without the recognized adverse effects of ANG II on glomerular filtration rate, renal blood flow, oxidative stress, vascular reactivity, proteinuria, and injury-related gene expression; renal HO activity is essential in preserving perfusion of the ANG II-exposed kidney. These findings represent an uncommon example wherein function of a stressed organ (by ANG II), but not that of the unstressed organ, requires intact renal HO activity, even when the imposed stress neither induces HO-1 nor HO activity. These findings may be germane to conditions attended by heightened ANG II levels, ineffective renal perfusion, and susceptibility to acute kidney injury. tin mesoporphyrin; ischemia ANG II IS A MAJOR CONTRIBUTOR to chronic kidney disease by virtue of its hemodynamic, proinflammatory, and profibrotic effects. Indeed, agents that interrupt the generation of ANG II and the engagement of ANG II with its receptor comprise a fundamental therapeutic approach in the management of patients with chronic kidney disease (12,20,22). Such therapies, however, reduce but do not abort the progression of chronic kidney disease, and thus complementary strategies that can synergize with these therapies would be of interest. In this regard, a fundamental basis for the injurious effects of ANG II involves the imposition of oxidant stress via NADPH oxidase (35). Studies by us and others have demonstrated that ANG II induces the antioxidant gene heme oxygenase-1 (HO-1) (3, 4, 11) in the kidney in vivo and in vitro and that such induction of HO-1, by virtue of its antioxidant, anti-inflammatory, and vasorelaxant properties (1,2,15,24), is implicated as an adaptive, protective mechanism that can reduce the severity of ANG II-induced renal injury.An established approach employed in studying the pathogenetic basis for ANG II-induced renal injury utilizes the chronic administration of ANG II by osmotic minipumps. Such studies demonstrate that ANG II, so administered, provokes markedly i...

Inhibition of heme oxygenase augments tubular sodium reabsorption

“…In addition, CrMP acutely decreases renal HO-1 levels. The present study determined that renal HO-1 protein levels decreased; however, HO-1 activity was not determined as previously reported (21). In addition, previous studies observed an increase in HO protein during administration of Sn-protoporphyrin while the current study observed a decrease in HO-1 protein with CrMP (27).…”

Renal Inhibition of Heme Oxygenase-1 Increases Blood Pressure in Angiotensin II-Dependent Hypertension

“…Our finding that inhibition of HO activity in Ang II-infused mice exacerbates the blood pressure response and increases cardiac hypertrophy despite the lack of effect of Ang II on HO activity and protein in the kidney being similar to that recently described in a model of low Ang II infusion in the rat [ 24 ]. In this study, inhibition of HO activity resulted in increased renal vascular resistance and decreased renal blood flow in Ang II-infused rats despite no measureable changes in HO activity or protein in the kidney with the dose of Ang II-infused in the study.…”

“…Similar effects on renal vascular resistance and blood flow were not observed in control rats in which HO was blocked. Interestingly, inhibition of HO activity resulted in a lowering of blood pressure in the Ang II-infused rats in this study as measured acutely under anesthesia [ 24 ]. While the differences in blood pressure responses between the studies could be due to species differences or differences in the way in which blood pressures were measured, the results from these two studies lend support for the hypothesis that HO-1 plays an important role in the stress response of the kidney even in conditions in which its activity is not significantly increased.…”

Induction and functional significance of the heme oxygenase system in pathological shear stress in vivo

“…HO activity in mouse aortas was determined as described in our previous study (45) in which the rate of generation of bilirubin from hemin was measured. Briefly, aortas were homogenized in 0.2 ml of 0.1 M potassium phosphate (pH 7.4) containing 2 mM MgCl 2, and homogenates were centrifuged at 12,000 g for 15 min.…”