AbstractAquaporin‐8 (AQP8) is a water channel expressed extensively in male and female reproductive systems. But its physiological functions are largely unknown. In the present study, we first found significantly increased number of offspring delivered by AQP8−/− mothers compared with wild‐type mothers in cross‐mating experiments. Comparison of ovulation in the two genotypes demonstrated that AQP8−/− ovaries released more oocytes (9.5 ± 1.9 vs. 7.1 ± 2.1 in normal ovulation and 37.8 ± 6.7 vs. 27.9 ± 5.7 in superovulation). Histological analysis showed increased number of corpus luteums in mature AQP8−/− ovaries, suggesting increased maturation and ovulation of follicles. By RT‐PCR, western blot and immunohistochemistry analyses, we determined the expression of AQP8 in mouse ovarian granulosa cells. Granulosa cells isolated from AQP8−/− mice showed 45% of decreased membrane water permeability than wild‐type mice. As the atresia of ovarian follicles is primarily due to apoptosis of granulosa cells, we analyzed the apoptosis of isolated granulosa cells from wild‐type and AQP8−/− mice. The results indicated significantly lower apoptosis rate in AQP8−/− granulosa cells (21.3 ± 3.6% vs. 32.6 ± 4.3% in AQP8+/+ granulosa cells). Taken together, we conclude that AQP8 deficiency increases the number of mature follicles by reducing the apoptosis of granulosa cells, thus increasing the fertility of female mice. This discovery may offer new insight of improving female fertility by reducing granulosa cell apoptosis through AQP8 inhibition. © IUBMB IUBMB Life, 62(11): 852–857, 2010.