Induction of hemeoxygenase‐1 slows the progression of hypertension and proteinuria in spontaneously hypertensive rats

Abstract

The renoprotective mechanisms of hemeoxygenase‐1 (HO‐1) induction remain unclear. We hypothesize that induction of HO‐1 will decrease blood pressure and proteinuria in spontaneously hypertensive rats (SHR) via antioxidant and anti‐inflammatory mechanisms. Male WKY and SHR were injected with the HO‐1 inducer cobalt protoporphrin (CoPP, 1.5 mg/kg s.c. bi‐weekly) for two weeks. CoPP reduced mean arterial pressure (MAP) (133±2 vs. 144±4 mmHg, p<0.05) and proteinuria (24±2 vs. 14±1mg/day, p<0.05) in SHR rats compared to baseline values, with no effect in WKY. Renal cortical superoxide (O2−) production and urinary 8‐isoprostane excretion were higher in SHR compared to WKY (O2−: 10.5±1 vs.6±1 CPM/mg protein, p<.05; 8‐iso: 7±1.3 vs. 3.4±0.8 ng/day, p<0.05) and CoPP attenuated oxidative stress levels in SHR only (O2−: 5.1±1 CPM/mg, p<0.05; 8‐iso: 4.4±0.7 ng/day). SHR showed a marked elevation in urinary MCP‐1 excretion compared with WKY (19±2 vs. 7.5±2.5 ng/day, p<0.05) and this was attenuated by induction of HO‐1 in SHR (10.5±2.7 ng/day). Plasma nitrite was reduced in SHR compared to WKY (7.9±1.1 vs. 12.7±1.5 μM, p<0.05) and HO‐1 induction increased plasma nitrite levels in SHR (17.5±2.9 μM). These data demonstrate that induction of HO‐1 slows the progression of hypertension and proteinuria in SHR. These changes were associated with reduced renal oxidative stress and inflammation and increased indices of nitric oxide.