Expression and localization of apelin and its receptor in the testes of diabetic mice and its possible role in steroidogenesis

Type 1 diabetes mellitus (T1DM) is a metabolic disorder with severe hyperglycemia, one of the complications of which is testicular dysfunctions, androgen deficiency and decreased male fertility. In the diabetic testes, the expression and signaling pathways of leptin and a number of other adipokines are significantly changed. However, there is no information on the localization and expression of adipokine, apelin and its receptor (APJ) in the diabetic testes, although there is information on the involvement of apelin in the regulation of reproductive functions. The aim of this study was to investigate the expression and localization of apelin and APJ in the testes of mice with streptozotocin-induced T1DM and to estimate the effects of agonist (apelin-13) and antagonist (ML221) of APJ on the testosterone production by diabetic testis explants in the in vitro conditions. We first detected the expression of apelin and its receptor in the mouse testes, and showed an increased intratesticular expression of apelin and APJ along with the reduced testosterone secretion in T1DM. Using imunohistochemical approach, we showed that apelin and APJ are localized in the Leydig and germ cells, and in diabetes, the amount of these proteins was significantly higher than in the control mice. The diabetic testes had a decrease in germ cell proliferation (the reduced PCNA and GCNA levels) and an increase in apoptosis (the increased active caspase-3 and decreased BCL2 levels). These results suggest an involvement of apelin and APJ in T1DM-induced testicular pathogenesis. Treatment of the cultured testis explants with ML221 significantly increased the testosterone secretion, whereas apelin-13 was ineffective. Thus, hyperapelinemia in the testes can significantly contribute to testicular pathogenesis in T1DM, and pharmacological inhibition of apelin receptors can improve testicular steroidogenesis.