Induction of hemeoxygenase-1 attenuates the hypertension and renal inflammation in spontaneously hypertensive rats.
The reno-protective mechanisms of hemeoxygenase-1 (HO-1) induction in hypertension remain unclear. We hypothesize that induction of HO-1 will decrease blood pressure and proteinuria with a marked decrease in oxidative stress and inflammation in spontaneously hypertensive rats (SHR). Male Wistar Kyoto (WKY) and SHR were injected with the HO-1 inducer cobalt protoporphyrin (CoPP, 1.5 mg/kgs.c. twice weekly) which resulted in an increase in renal HO-1 expression after 2 weeks. CoPP reduced mean arterial pressure (133±2 mmHg vs. 144±4 mmHg, p<0.05) and proteinuria (14±1 mg/day vs. 24±2 mg/day, p<0.05) in SHR as compared to baseline values, with no effect in WKY. Renal cortical superoxide (O(2)(-)) production and urinary 8-isoprostane excretion were higher in SHR compared to WKY (O(2)(-): 11±1 CPM/μg vs. 6±1 CPM/μg protein, p<0.05; 8-iso: 7±1 ng/day vs. 3±0.8 ng/day, p<0.05) and CoPP attenuated oxidative stress levels only in SHR (O(2)(-): 5±1 CPM/μg, p<0.05; 8-isoprostane: 4±0.7 ng/day) without an overall effect on antioxidant defense enzymes expression and activities. SHR showed a marked elevation in plasma C-reactive protein (CRP) and urinary monocyte chemoattractant protein-1 (MCP-1) excretion compared with WKY and HO-1 induction reduced the CRP and MCP-1 levels in SHR. Cortical COX2 expression and urinary thromboxane B(2) (TXB(2)) excretion were also significantly elevated in SHR compared to WKY and levels were reduced with induction of HO-1. Inhibition of HO with stannous mesoporphyrin further increased blood pressure and proteinuria in SHR and blocked the ability of CoPP to reduce blood pressure and proteinuria in SHR. These data demonstrate that induction of HO-1 slows the progression of hypertension and proteinuria in SHR and these changes were associated with reduced renal oxidative stress and inflammation.
Elmarakby
Ahmed A
AA
Vascular Biology Center, Medical College of Georgia, Augusta, GA 30912, United States. aelmarakby@mcg.edu
Faulkner
Jessica
J
Posey
Sam P
SP
Sullivan
Jennifer C
JC
D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D002374:Catalase / Q000378:metabolism; D004790:Enzyme Induction; D051547:Heme Oxygenase-1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006973:Hypertension / Q000188:drug therapy / Q000201:enzymology / Q000503:physiopathology*; D007249:Inflammation / Q000188:drug therapy*; D007668:Kidney / Q000378:metabolism / Q000503:physiopathology*; D008297:Male; D008665:Metalloporphyrins / Q000008:administration & dosage / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects; D011524:Protoporphyrins / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D013482:Superoxide Dismutase / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism / Q000494:pharmacology
D000975:Antioxidants; D008665:Metalloporphyrins; D011524:Protoporphyrins; C518404:stannous mesoporphyrin; D013481:Superoxides; C007095:cobaltiprotoporphyrin; D002374:Catalase; D051547:Heme Oxygenase-1; D013482:Superoxide Dismutase