Mas receptor signalling supports spermatogenesis and protection against diabetic testicular injury in mice

Abstract Background The angiotensin-(1–7)/Mas receptor (MasR) axis has been implicated in male reproduction, but its pharmacological modulation in metabolic testicular injury remains incompletely characterised. We combined human sperm analyses, genetic and pharmacological loss-of-function experiments, and AVE0991 treatment in a diabetic mouse model. Methods Sperm samples from 10 normozoospermic and 10 asthenozoospermic men were analysed in assay-specific subsets. Acute AVE0991 responses were examined ex vivo. Reproductive endpoints were assessed in global Mas1 -null mice, adult wild-type mice receiving A779 (0.05 mg/kg/day), and streptozotocin-induced diabetic mice receiving AVE0991 (0.6 mg/kg/day) for six weeks. AVE0991 was also administered to non-diabetic Mas1 -null mice. Continuous endpoints were analysed using t-tests or analysis of variance with multiplicity adjustment where applicable; mating outcomes were descriptive. Results MasR protein abundance and immunofluorescence signal were lower in the small asthenozoospermic sperm subsets. RNA assays showed lower relative MAS1 signals, with interpretation limited by RNA composition and assay specificity. AVE0991 at 0.1 or 1 nM transiently increased progressive motility, whereas 10 nM showed a decrease. A779 attenuated the motility response and the calcium response. AVE0991 was also associated with fewer acrosome-reacted spermatozoa and higher phosphorylated PI3K and AKT signals. Mas1 -null mice and A779-treated wild-type mice showed impaired seminiferous architecture and reduced sperm parameters. In diabetic mice, AVE0991 partially improved histology and sperm concentration and motility without restoring testicular AKT phosphorylation. No comparable improvement was evident in the non-diabetic knockout arm. Conclusions The findings support a role for MasR signalling in normal spermatogenesis and suggest a preclinical benefit of AVE0991 in diabetic testicular injury. The human findings are exploratory. The study does not establish a PI3K/AKT-mediated protective mechanism or definitively demonstrate receptor dependence of the diabetic treatment response.