Hydrogen Sulfide Protects Hyperhomocysteinemia-Induced Renal Damage by Modulation of Caveolin and eNOS Interaction

Abstract

The accumulation of homocysteine (Hcy) during chronic kidney failure (CKD) can exert toxic effects on the glomeruli and tubulo-interstitial region. Among the potential mechanisms, the formation of highly reactive metabolite, Hcy thiolactone, is known to modify proteins by N-homocysteinylation, leading to protein degradation, stress and impaired function. Previous studies documented impaired nitric oxide production and altered caveolin expression in hyperhomocysteinemia (HHcy), leading to endothelial dysfunction. The aim of this study was to determine whether Hhcy homocysteinylates endothelial nitric oxide synthase (eNOS) and alters caveolin-1 expression to decrease nitric oxide bioavailability, causing hypertension and renal dysfunction. We also examined whether hydrogen sulfide (H2S) could dehomocysteinylate eNOS to protect the kidney. WT and Cystathionine β-Synthase deficient (CBS+/−) mice representing HHcy were treated without or with sodium hydrogen sulfide (NaHS), a H2S donor (30 µM), in drinking water for 8 weeks. Hhcy mice (CBS+/−) showed low levels of plasma H2S, elevated systolic blood pressure (SBP) and renal dysfunction. H2S treatment reduced SBP and improved renal function. Hhcy was associated with homocysteinylation of eNOS, reduced enzyme activity and upregulation of caveolin-1 expression. Further, Hhcy increased extracellular matrix (ECM) protein deposition and disruption of gap junction proteins, connexins. H2S treatment reversed the changes above and transfection of triple genes producing H2S (CBS, CSE and 3MST) showed reduction of vascular smooth muscle cell proliferation. We conclude that during Hhcy, homocysteinylation of eNOS and disruption of caveolin-mediated regulation leads to ECM remodeling and hypertension, and H2S treatment attenuates renovascular damage.

Role of Caveolin-1 in Diabetes and Its Complications

“…Recently Pushpakumar et al showed that homocysteinylation of eNOS and disruption of caveolin-mediated regulation leads to ECM remodeling and hypertension in mice. H 2 S treatment attenuated renovascular damage by modulating eNOS and CAV1 interaction and thus antagonizing ECM protein accumulation and smooth muscle cell proliferation [159].…”

Roles of Hydrogen Sulfide Donors in Common Kidney Diseases

“…Furthermore, the treatment of HHcy mice with 30 µM NaHS protects renal tissues from HHcy-induced inflammation and ROS by restoring MMPs/TIMPs and oxidized GSH/GSH status (Sen et al, 2009). NaHS also reduces the homocysteinylation of eNOS and stabilizes systolic BP, GFR, and connexins levels in HHcy mice (Pushpakumar et al, 2019). Based on the above information, there is a strong link between H 2 S and Hcy levels.…”

Hydrogen Sulfide and Carnosine: Modulation of Oxidative Stress and Inflammation in Kidney and Brain Axis

“…It causes arteriolar constriction, arterial stiffness, and endothelial damage [ 195 ]. H 2 S treatment in rodents attenuates renovascular damage by reducing hyperhomocysteinemia [ 196 ]. The pathophysiology of chronic kidney disease and neuropsychiatric disorders has been commonly associated with mechanisms related to the decreased availability of brain-derived neurotropic factor (BDNF) for renal and neuronal failure [ 197 ].…”