Nobiletin Ameliorates Testicular Dysfunction and Oxidative Stress through Modulation of the AT1R/gp91phox Pathway in 2K-1C Hypertensive Rats

Background Hypertension is a silent predator of reproductive health, often leading to testicular dysfunction through systemic oxidative stress. In this study, we explored the therapeutic potential of nobiletin, a bioactive hexamethoxyflavone derived from citrus peels, in reversing testicular dysfunction in two-kidney, one-clip (2K-1C) hypertensive rats. Methods Male Sprague–Dawley rats were subjected to right renal artery constriction to induce secondary hypertension. Three weeks after induction, rats were treated with either nobiletin at 15 or 30 mg/kg (NOB15 or NOB30) or losartan 10 mg/kg (LOS10) for 4 weeks. The angiotensin II receptor type I (AT 1 R)/NADPH oxidase subunit 2 (gp91 phox ) signaling pathway alongside testicular malondialdehyde (MDA) and plasma testosterone levels were the primary focus. Results In 2K-1C hypertensive rats, induced testicular dysfunction exhibited diminished sperm concentration, impaired motility, and reduced serum testosterone levels. However, nobiletin treatment resulted in a significant improvement in sperm quality. The improvement correlated with the suppression of AT 1 R/gp91 phox expression in 2K-1C untreated rats. Conclusions Nobiletin attenuates hypertension-induced testicular dysfunction by modulating the AT 1 R/gp91 phox pathway, which restores testosterone synthesis and sperm viability. These findings identify nobiletin as a promising natural alternative for managing hypertension-linked infertility.