Co-administration of subtherapeutic doses of yohimbine and NaHS potentially ameliorates CKD-induced necroptosis by modulating RAAS/ROS imbalance, sympathetic overactivity, and inflammation.

Chronic kidney disease is marked by increased sympathetic activity, inflammation, RAAS activation, and oxidative stress, promoting necroptosis. This study explores the potential of co-administering yohimbine and sodium hydrosulfide (NaHS) to reduce necroptosis, possibly by modulating RAAS/ROS imbalance, sympathetic overactivity, and inflammation. Male rats were assigned to five groups (n = 8): Sham, CKD, CKD + yohimbine, CKD + NaHS, and CKD + yohimbine + NaHS. CKD was induced via daily intraperitoneal adenine injections (50 mg/kg) for 4 weeks. After CKD induction, treatments included yohimbine (0.3 mg/L) and/or NaHS (15 μmol/L) in drinking water for another 4 weeks. After 8 weeks, urine samples were collected, and renal sympathetic nerve activity (RSNA), renal function, RAAS and norepinephrine levels, oxidative stress, inflammation, and necroptosis-related protein expression were assessed. CKD induction disrupted renal function and intensified RAAS/ROS imbalance, sympathetic overactivity, inflammation, and necroptosis through RIPK1-MLKL axis activation. Yohimbine alone reduced renal sympathetic nerve activity by approximately 18% and norepinephrine levels by 9% (p < 0.05). NaHS alone decreased plasma angiotensin II level by 9% (p < 0.05). Co-administration improved these three indices plus kidney function, oxidative stress and inflammation markers; downregulated angiotensin II Type I Receptor (AT1R), RIPK1, and MLKL proteins; and upregulated caspase-8 (p ≤ 0.05). In CKD, the interconnected RAAS/ROS imbalance and sympathetic-driven inflammation may activate necroptosis via the RIPK1-MLKL axis. Co-treatment with yohimbine and NaHS appeared to attenuate necroptosis, potentially by interfering with these pathological loops. Further studies are warranted to confirm these findings and elucidate the underlying mechanisms.