Gender Differences in Adenine Diet-Induced Kidney Toxicity: The Impact of 17β-Estradiol on Renal Inflammation and Fibrosis

Chronic kidney disease (CKD) involves ongoing impairment of kidney function and structural changes. Previous studies indicated that males have a substantially higher prevalence of CKD than those observed in females. Here, we compared the gender differences in CKD development by comparing age-matched male and female mice subjected to a 0.25% adenine diet (AD) for two weeks. Male mice showed a significantly greater decrease in kidney function than female mice, as evidenced by the elevated blood urea nitrogen levels (M-AD: 160 ± 5 mg/dL, F-AD: 90 ± 4 mg/dL; <i>p</i> < 0.001). Furthermore, male mice kidneys exhibited pronounced tubule dilation and kidney damage, as detected by histological and biochemical methods. The extent of fibrosis was quantified using multiple biological methods, revealing a greater degree of fibrosis in male kidneys. We next indicated the inflammatory responses in the kidneys. Similar to the extent of fibrosis, AD-fed male mice showed significantly increased levels of pro-inflammatory markers, including cytokine expression and infiltration of immune cell, compared to female mice. Based on in vivo observations, the anti-inflammatory and anti-fibrotic effects of 17β-estradiol (E2) were further evaluated in vitro conditions. E2 pre-treatment significantly reduced lipopolysaccharide-induced inflammatory response through inhibition of the nuclear factor-kappa B (NF-κB) pathway in NRK52E renal epithelial cells. In NRK49F renal fibroblasts, E2 pre-treatment also reduced TGFβ-induced fibrotic responses. We further demonstrated that E2 markedly decreased fibrosis and inflammation in AD-fed mouse kidneys. Our observations revealed that male mice kidneys exhibited a heightened inflammatory and fibrotic response compared to female mice kidneys. Additionally, our findings suggest that the observed sex differences may be partially attributed to the potential anti-inflammatory and anti-fibrotic effects of E2.