Faster rates of post-puberty kidney deterioration in males is correlated with elevated oxidative stress in males vs females at early puberty

Abstract

Background: Post-puberty deterioration of kidneys is more rapid in males than in females. To reveal the underlying molecular mechanisms for this difference, we analyzed gender-dependent gene expression in kidneys of three groups of 36 day-old rats.

Results: The number of genes exhibiting gender-dependent expression was highly influenced by the genetic background of the rat group examined. 373, 288 and 79 genes showed differential gene expression between males and females (p = 0.001) in US, Mhm and Mhm*BN rats, respectively. Of all gender dependently expressed genes, only 39 genes were differentially expressed in all tested groups and the direction of expression change was the same for those genes for all groups. The gene expression profile suggests higher metabolic and transport activities, enhanced cell proliferation, elevated oxidative stress, and altered vascular biology in males. Furthermore, elevated levels of superoxide anion (two- to three-fold) in males compared to females were detected at early puberty, but neither at pre-puberty nor at late puberty/early adulthood.

Conclusion: Our data suggest that early puberty, with gender-related elevation in oxidative stress in males, is a key compromising factor on kidneys in males.

Figure 1

The number of genes differentially expressed by gender was strongly influenced by genetic background. Gender-dependent gene expression was examined in kidneys of 36 day-old US, Mhm, and Mhm*BN rats with Affymetrix arrays Rae230A. In this Venn diagram the number of genes with gender-dependent expression (p = 0.001) in the respective groups is depicted.

Figure 2

The same tendency of gender-dependent expression change in all examined groups. Shown are microarray data for genes which were differentially expressed by gender in all three rat groups. For the two genes (Rgn and Sod3) with strongest expression changes between genders, the microarray data were confirmed by real-time PCR in Mhm rats.

Figure 3

Elevated superoxide anion in males at early puberty compared with females. ROS was examined in the glomeruli of 36 day-old SD and Mhm rats. Superoxide anion was significantly higher in males compared with females. Males had the tendency to produce more total ROS, but the gender difference was not statistically significant.

Figure 4

Development of the gender difference in ROS with age. Total ROS rose at early puberty and remained at the elevated level during late puberty/early adulthood, without significant differences between genders. At pre-puberty and at late puberty/early adulthood, superoxide anion did not differ significantly between genders. Superoxide anion peaked at early puberty, more abruptly in males than in females (p = 0.05), and dropped to pre-puberty levels as late puberty/early adulthood approached.

Figure 5

Reduced anti-oxidation via Sod3 in males compared with females. A: Gender difference in ROS was examined in glomeruli of 36 day-old Mhm rats, perfused with heparin in PBS or with PBS alone. The elevation of ROS in males is shown on the y-axis (expressed as the ratio of male vs. female). In PBS-perfused kidneys, the elevation of superoxide anion in males was statistically significant. This statistical significance diminished when kidneys were flushed with heparin. Also the elevation of total ROS in males attenuated (the ratio of male vs. female became smaller). B: Real-time PCR confirmed significant under-expression of Sod3 in males compared with females (p < 0.01).

Figure 6

The proposed mechanism underlying the gender difference in kidney function at early puberty. Male gender stimulates growth and proliferation, enhances metabolic and transport activities and therefore elevate oxidative stress. Elevated oxidative stress in form of chronic tubulointerstitial hypoxia causes renal failure by altering tissue structures and function such as the vascular biology by elevating blood pressure, damaging vessels and enhancing blood coagulation.