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

Abstract

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&#x2009;=&#x2009;8): Sham, CKD, CKD + yohimbine, CKD + NaHS, and CKD + yohimbine + NaHS. CKD was induced via daily intraperitoneal adenine injections (50&#xa0;mg/kg) for 4&#xa0;weeks. After CKD induction, treatments included yohimbine (0.3&#xa0;mg/L) and/or NaHS (15&#xa0;&#x3bc;mol/L) in drinking water for another 4&#xa0;weeks. After 8&#xa0;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&#x2009;<&#x2009;0.05). NaHS alone decreased plasma angiotensin II level by 9% (p&#x2009;<&#x2009;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&#x2009;&#x2264;&#x2009;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.