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Abstract: TH-PO799

Gender Differences in the Development of Glomerulopathy in Mice with an EGFR Gain-of-Function Mutation

Session Information

Category: Glomerular Diseases

  • 1201 Glomerular Diseases: Fibrosis and Extracellular Matrix

Authors

  • Zhang, Ming-Zhi, Vanderbilt University Medical Center, Nashville, Tennessee, United States
  • Li, Yan, Vanderbilt University Medical Center, Nashville, Tennessee, United States
  • Li, Zhilian, Vanderbilt University Medical Center, Nashville, Tennessee, United States
  • Wang, Suwan, Vanderbilt University Medical Center, Nashville, Tennessee, United States
  • Wang, Yinqiu, Vanderbilt University Medical Center, Nashville, Tennessee, United States
  • Niu, Aolei, Vanderbilt University Medical Center, Nashville, Tennessee, United States
  • Fan, Xiaofeng, Vanderbilt University Medical Center, Nashville, Tennessee, United States
  • Harris, Raymond C., Vanderbilt University Medical Center, Nashville, Tennessee, United States
Background



The epidermal growth factor receptor (EGFR) is widely expressed in the kidney in both glomeruli and tubules. Under pathological conditions, persistent and dysregulated EGFR activation mediates progressive glomerular and tubulointerstitial injury in progressive kidney diseases. Although gender differences mediating predisposition to kidney injury are well known, no previous studies have investigated the potential role of EGFR in these differences.

Methods


Dsk5 mice have a Leu863Gln mutation within a region of the kinase domain that stabilizes the receptor activation loop, producing a gain-of-function allele that increases basal EGFR kinase activity. Both male and female heterozygous Dsk5 mice on the 129 background were used. Dsk5 mice were oopherectomized or castrated before puberty to investigate the effect of sex hormones on EGFR expression and glomerulopathy.

Results

In male Dsk5 mice constitutive EGFR activation was confirmed by intense phospho-EGFR immunostaining not seen in wild type mice. At 15 weeks of age, male Dsk5 mice exhibited glomerulopathy, with mesangial proliferation and segmental and global sclerosis. They also had increased albuminuria, loss of podocytes and increased tubulointerstitial fibrosis as indicated by Sirius red and Masson’s trichrome staining. Kidneys had increased mRNA and protein levels of profibrotic and fibrotic components, including TGF-β, α-smooth muscle actin, connective tissue growth factor, fibronectin, collagens I, III, IV and increased immune cell infiltration and proinflammatory cytokines/chemokines, such as MCP-1, TNF-α, IL-6, and IL-1α. Unexpectedly, there was minimal kidney injury in female Dsk5 mice at up to 30 weeks of age. Renal mRNA and protein EGFR levels were significantly lower in age-matched females than males. Oopherectomy had no effect on renal EGFR levels and injury in female Dsk5 mice, while castration protected against the kidney injury seen in intact male Dsk5 mice, in association with a reduction in EGFR expression to levels seen in female mice.

Conclusion



These studies indicate that constitutive EGFR activation promotes glomerular and tubulointerstitial injury in male mice, but not in female mice, and this gender difference may be at least in part due to androgen-dependent higher basal levels of EGFR expression.

Funding

  • NIDDK Support