Hemin therapy attenuates kidney injury in deoxycorticosterone acetate-salt hypertensive rats.
Upregulating the heme oxygenase (HO) system removes the prooxidant heme, and thus is cytoprotective. Additionally, the products from the HO pathway including, carbon monoxide, bilirubin, and biliverdin, scavenge reactive oxygen species, inhibit lipid peroxidation, and suppress tissue inflammation, while the iron formed enhances the synthesis of the antioxidant ferritin. Deoxycorticosterone acetate (DOCA)-salt hypertension, a model of human primary aldosteronism, causes oxidative stress and impairs renal function by stimulating inflammatory/oxidative transcription factors such as NF-kappaB and activating protein (AP-1). The effect of the HO system in end-organ damage in mineralocorticoid-induced hypertension has not been fully characterized. In this study, the administration of the HO inducer hemin lowered blood pressure (191 vs. 135 mmHg; n = 22, P < 0.01), increased creatinine clearance, and reduced kidney hypertrophy proteinuria, albuminuria, and histopathological lesions, including glomerular hypertrophy, glomerulosclerosis, tubular dilation, tubular cast formation, and interstitial mononuclear cell infiltration in nephrectomy/DOCA-high-salt-hypertension. The renoprotection was accompanied by reduced levels of NF-kappaB, AP-1, fibronectin, transforming growth factor (TGF)-beta, and 8-isoprostane, a marker of oxidative stress. Correspondingly, a robust increase in total antioxidant capacity, HO activity, cGMP, and an antioxidant like ferritin was observed in hemin-treated animals. Our findings suggest that suppression of oxidative/inflammatory insults alongside the corresponding decline of fibronectin and TGF-beta, an activator of extracellular matrix proteins, may account for the attenuation of renal histopathological lesions and the antihypertrophic effects of hemin. The multifaceted interaction among the HO system, TGF-beta, fibronectin, AP-1, and NF-kappaB may be explored to design new drugs against end-stage-organ damage.
Jadhav
Ashok
A
Department of Physiology, College of Medicine, University of Saskatchewan, Saskatoon, Saskatchewan, Canada.
Torlakovic
Emina
E
Ndisang
Joseph Fomusi
JF
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D006152:Cyclic GMP / Q000378:metabolism; D003900:Desoxycorticosterone; D005293:Ferritins / Q000378:metabolism; D006419:Heme Oxygenase (Decyclizing) / Q000378:metabolism*; D006427:Hemin / Q000494:pharmacology / Q000627:therapeutic use*; D006973:Hypertension / Q000139:chemically induced / Q000150:complications / Q000188:drug therapy*; D006984:Hypertrophy / Q000517:prevention & control; D007668:Kidney / Q000187:drug effects / Q000473:pathology; D007674:Kidney Diseases / Q000201:enzymology / Q000209:etiology / Q000517:prevention & control*; D008297:Male; D016328:NF-kappa B / Q000378:metabolism; D009392:Nephrectomy; D018384:Oxidative Stress / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D018808:Transcription Factor AP-1 / Q000378:metabolism; D015854:Up-Regulation
D016328:NF-kappa B; D018808:Transcription Factor AP-1; D003900:Desoxycorticosterone; D006427:Hemin; D005293:Ferritins; D006419:Heme Oxygenase (Decyclizing); D006152:Cyclic GMP