Upregulating the heme oxygenase (HO) system removes the prooxidant heme, and thus 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-B and activating protein (AP-1). The effect of the HO system in end-organ damage in mineralcorticoid-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-B, AP-1, fibronectin, TGF- and 8-isoprostane, a marker of oxidative stress. Correspondingly, robust increase in the 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-, an activator of extracellular matrix proteins may account the attenuation of renal histopathological lesions and the anti-hypertrophic effects of hemin. The multifaceted interaction between the HO system, TGF-, fibronectin, AP-1 and NF-B may be explored to design new drugs against end-stage-organ damage.