Disruption of NHE8 expression impairs Leydig cell function in the testes

Abstract

Multiple sodium/hydrogen exchanger (NHE) isoforms are expressed in the testes, and they play various roles in cell volume regulation, intracellular pH regulation, and fluid absorption. NHE8, the most recently characterized NHE family member, is detected in the Leydig cells in humans and mice in great abundance by immunohistochemistry in the current study. Male mice lacking NHE8 expression were infertile. Despite having intact male reproductive organs, male NHE8 Ϫ/Ϫ mice have smaller testes and lacked spermatozoon in the seminiferous tubules and the epididymis. At the age of 39 wk, few spermogonia were seen in the testis in NHE8 Ϫ/Ϫ mice. Although male NHE8 Ϫ/Ϫ mice have normal serum levels of luteinizing hormone and follicle-stimulating hormone, serum testosterone level was significantly reduced. These mice have decreased expression of luteinizing hormone receptor in the testes. In NHE8 small-interfering RNA-transfected mouse Leydig cells (MLTC-1), silencing of NHE8 decreased the expression of luteinizing hormone receptor by ϳ70%. Moreover, loss of NHE8 function in Leydig cells resulted in disorganized luteinizing hormone receptor membrane distribution. Therefore, male infertility in NHE8 Ϫ/Ϫ mice is at least partially due to the disruption of luteinizing hormone receptor distribution and consequent low testosterone production, which leads to Sertoli cell dysfunction. Our work identified a novel role of NHE8 in male fertility through its effect on modifying luteinizing hormone receptor function.

Loss of the Na+/H+ exchanger NHE8 causes male infertility in mice by disrupting acrosome formation

“…Ϫ/Ϫ mice never produced progeny, as reported previously (26,30). Vaginal plugs observed in breedings with male Nhe8 Ϫ/Ϫ mice indicated normal mating behavior, libido, copulation, and ejaculation.…”

“…Although we unambiguously identified a germ cell-intrinsic defect in acrosome formation as underlying the male infertility of Nhe8 Ϫ/Ϫ mice, Xu et al (30) recently suggested that it is caused by reduced testosterone levels stemming from impaired trafficking of the luteinizing hormone receptor in Leydig cells.…”

“…The authors state that NHE8 is mainly expressed in Leydig cells (30), without, however, using Nhe8 Ϫ/Ϫ controls as done here. Disconcertingly, they also observed smaller testes and azoospermia.…”

“…NHE8 was also reported to be present on multivesicular bodies (23) and somewhat surprisingly at the apical brush-border membrane of epithelial cells of the intestine and renal proximal tubules (22,24,25). Nhe8 Ϫ/Ϫ mice show impaired colonic mucin synthesis and bicarbonate secretion (26,27), a dysfunction of the retinal pigment epithelium (28,29), and male infertility (28,30). In addition to NHE8, two other NHEs are known to affect male fertility in mice.…”

Sodium-Hydrogen-Exchanger expression in human sperm and its relationship with semen parameters

“…Several isoforms of NHE have been demonstrated to play a role in male reproduction. For example, disruption of NHE8 expression could result in impaired Leydig cell function and smaller testes, as well as fewer spermatozoa [11]. Interestingly, three NHEs have been identified in spermatozoa, namely NHE1, NHE5, and NHE10 (spermspecific NHE isoform, sNHE) [12,13].…”