HO-1 modulates obesity-related renal sodium metabolism via oxidative stress and Na/K-ATPase signaling

The dysregulation of renal sodium metabolism linked to obesity and excessive dietary salt intake is a significant factor in the development of salt-sensitive hypertension. Our previous research has demonstrated that oxidative stress—particularly through the amplification loop of reactive oxygen species (ROS)—plays a critical role in modulating renal sodium handling via Na/K-ATPase signaling. This present study aims to determine whether the antioxidant enzyme heme oxygenase-1 (HO-1) modulates renal sodium metabolism by affecting oxidative stress and the Na/K-ATPase pathway, potentially revealing novel therapeutic avenues. To investigate this, we conducted high-salt dietary interventions and administered Co(III) protoporphyrin IX chloride (CoPP) in both normal and obese C57BL/6J mice. Results indicated that obesity exacerbated oxidative stress and disrupted sodium metabolism. Notably, the induction of HO-1 via CoPP effectively reduced oxidative stress, suppressed inflammatory responses, and modulated mechanisms of renal sodium handling. These observations were corroborated by decreases in protein carbonylation and malondialdehyde (MDA) levels, as well as inhibition of the IL-6/STAT3 inflammatory pathway. Importantly, up-regulation of HO-1 corresponded with a reduction in activated Na/K-ATPase signaling, likely attributable to diminished ROS levels. Furthermore, genetic analyses and urinary metabolite profiles validated the regulatory effects of CoPP on oxidative stress and sodium metabolism. In conclusion, our findings elucidate the dual role of HO-1 as both an antioxidant defense system and a pivotal modulator of sodium excretion. This research underscores the multifaceted physiological functions of HO-1 and its crucial role in regulating renal sodium metabolism, with significant implications for managing salt-sensitive hypertension.