Age-associated increase in AT₁R expression in human testis and its intervention effects on Leydig cell senescence in aged rodents

The active peptide hormone Ang II (angiotensin II) mediates the vast majority of the RAS (renin-angiotensin system) action, mainly through activation of AT₁R (Angiotensin II type-1 receptor). AT₁R expression peaks in newborn males and decreases toward the adult age, and it is shown to exhibit an inhibitory effect on hCG (human chorionic gonadotropin)-stimulated steroidogenesis in LCs (Leydig cells), as well as an promoting effect on smooth muscle and endothelial cell senescence. However, whether hyperactivation of the AT₁R signaling exerts any effects on Leydig cell senescence, which could provide insights into hypogonadism mechanisms for aging males, remains unexplored. We herein reported that AT₁R expression was significantly upregulated in aged human and rat testes. Transgenic overexpression of AT₁R in LCs mimicked multiple late-onset hypogonadism phenotypes, including acceleration of Leydig cell senescence, defective steroidogenesis and spermatogenesis, and increased inflammation and oxidative stress. One of the core biochemical events underpinning AT₁R action was the AT₁R-induced enhancement of the interaction between MDM2 (murine double minute 2) and the p65 subunit of NF-κB (nuclear factor-kappaB), consequently augmenting polyubiquitination and activation of p65, in a p38-dependent manner. Conversely, repression of AT₁R activity ameliorated Leydig cell senescence and rescued testicular steroidogenesis in old rats. Together, forced expression of AT₁R within the testicular interstitium potentiates aging-related traits in LCs, thereby leading to fertility impairment with defective steroidogenesis and spermatogenesis in male rodents. Our systematic analysis also indicates that blocking the Ang II/AT₁R signal might be beneficial in intervening disorders of late-onset hypogonadism in old males.