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Abstract: TH-PO186

Assessing the Influence of Sex on the CD1 Nephrectomized Streptozotocin-Induced Diabetic Kidney Disease Model

Session Information

Category: Diabetic Kidney Disease

  • 601 Diabetic Kidney Disease: Basic

Authors

  • Nmecha, Ifeanyi Kennedy/k, McMaster University Faculty of Health Sciences, Hamilton, Ontario, Canada
  • Trink, Jackie, McMaster University Faculty of Health Sciences, Hamilton, Ontario, Canada
  • Zhang, Dan, McMaster University Faculty of Health Sciences, Hamilton, Ontario, Canada
  • Gao, Bo, McMaster University Faculty of Health Sciences, Hamilton, Ontario, Canada
  • Macdonald, Melissa, McMaster University Faculty of Health Sciences, Hamilton, Ontario, Canada
  • Krepinsky, Joan C., McMaster University Faculty of Health Sciences, Hamilton, Ontario, Canada
Background

Diabetic kidney disease (DKD) is the leading cause of kidney failure in North America. DKD is characterized by a progressive increase in albuminuria, glomerular hypertrophy, expansion of the glomerular mesangium, thickening of the glomerular basement membrane, and tubulointerstitial fibrosis and atrophy. Recent studies have shown that sex and sex hormones are important factors to consider in the development and progression of DKD. Presently, the hallmarks of this disease have primarily been studied in male rodent models. Here we explored the influence of sex in the CD1 nephrectomized streptozotocin (STZ)-induced murine model.

Methods

To induce DKD, 8-week-old CD1 mice underwent a right nephrectomy. After 1 week of recovery, they were injected IP with 200mg/kg STZ and followed for 12 weeks. Outcomes included urinary albumin-to-creatinine ratio (ACR), blood pressure (BP), weight, kidney and glomerular hypertrophy and kidney pathology.

Results

STZ dose required reduction in females to 150mg/kg due to high initial mortality. However, females often required reinjection after 2 weeks at 100mg/kg to induce hyperglycemia. Males had a greater decrease in endpoint weight and increase in BP. Both sexes developed comparable hyperglycemia, kidney hypertrophy and albuminuria, although ACR was more variable in females. Glomerular hypertrophy was more pronounced in male diabetics, as was basement membrane thickening. Serum TGFβ1 levels were increased only in females, which may be related to their known greater TGFβ1 production after puberty compared to male mice. However, urine TGFβ1 increased comparably in both sexes. Accumulation of profibrotic proteins fibronectin and collagens I, III, IV, and markers of T-cell and macrophage infiltration were also similar between sexes.

Conclusion

Female mice required a modification of the STZ protocol to maintain survival, but induce hyperglycemia. While somewhat more pronounced in male mice, both sexes developed typical characteristics of DKD. Future studies evaluating the potential of therapeutic interventions can thus be assessed in both sexes in this model of DKD.

Funding

  • Government Support – Non-U.S.