The Role of the EGF Receptor in Sex Differences in Kidney Injury

Significance Statement Sex differences in the predisposition to CKD development or progression are well known. However, the underlying mechanisms involved remain unclear. The authors found markedly greater renal EGF receptor (EGFR) expression levels in adult wild-type male versus female mice, and a similar sex difference in EGFR expression in normal adult human kidneys. In Dsk5 mutant mice with constitutive EGFR activation, males developed significant spontaneous glomerular and tubulointerstitial injury, whereas females were relatively spared. In female mice, oophorectomy did not affect renal EGFR expression, but testosterone increased it; in male mice, castration decreased renal EGFR expression. These findings indicate that differential expression in renal EGFR expression plays a role in sex differences in susceptibility to progressive kidney injury, one that may be mediated in part by testosterone. Background Sex differences mediating predisposition to kidney injury are well known, with evidence indicating lower CKD incidence rates and slower decline in renal function in nondiabetic CKD for premenopausal women compared with men. However, signaling pathways involved have not been elucidated to date. The EGF receptor (EGFR) is widely expressed in the kidney in glomeruli and tubules, and persistent and dysregulated EGFR activation mediates progressive renal injury. Methods To investigate the sex differences in response to renal injury, we examined EGFR expression in mice, in human kidney tissue, and in cultured cell lines. Results In wild type mice, renal mRNA and protein EGFR levels were comparable in males and females at postnatal day 7 but were significantly lower in age-matched adult females than in adult males. Similar gender differences in renal EGFR expression were detected in normal adult human kidneys. In Dsk5 mutant mice with a gain-of-function allele that increases basal EGFR kinase activity, males had progressive glomerulopathy, albuminuria, loss of podocytes, and tubulointerstitial fibrosis, but female Dsk5 mice had minimal kidney injury. Oophorectomy had no effect on renal EGFR levels in female Dsk5 mice, while castration protected against the kidney injury in male Dsk5 mice, in association with a reduction in EGFR expression to levels seen in females. Conversely, testosterone increased EGFR expression and renal injury in female Dsk5 mice. Testosterone directly stimulated EGFR expression in cultured kidney cells. Conclusions These studies indicate that differential renal EGFR expression plays a role in the sex differences in susceptibility to progressive kidney injury that may be mediated at least in part by testosterone.