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Abstract: SA-PO224

Gender Affects Diabetes and Diabetic Nephropathy Development in KKAy Mice

Session Information

Category: Diabetic Kidney Disease

  • 601 Diabetic Kidney Disease: Basic

Authors

  • Van Koppen, Arianne, TNO, Leiden, South Holland, Netherlands
  • Nawrocki, Andrea R., Janssen Global Services LLC, Titusville, New Jersey, United States
  • Nguyen, Tri Q., Universitair Medisch Centrum Utrecht Afdeling Pathologie, Utrecht, Utrecht, Netherlands
  • Hinke, Simon A., Janssen Global Services LLC, Titusville, New Jersey, United States
  • Stoop, Reinout, TNO, Leiden, South Holland, Netherlands
Background

We are developing a translational mouse model of advanced diabetic nephropathy which resembles both pathophysiology and pathology of the human situation. Diabetes affects men and women differently but treatment guidelines remans equal. Understanding gender differences is key to develop personalized therapeutics. We aim to study how gender influences diabetes induction and development of diabetic nephropathy in mice.

Methods

Male and female KKAy mice of 8 weeks underwent a uninephrectomy. After recovery, all mice were fed a high fat diet (HFD). Females received 100 mg/L LNNA in drinking water. Males were split in two groups and received either 50 or 100mg/L LNNA in drinking water. Body weight, food and water and blood glucose were monitored regularly. GFR by FITC-inulin clearance was measured transdermal. Albuminuria, BUN and organ weights were measured terminally. Pathology was scored by renal pathologists. KK females were used as non-induced control mice.

Results

Despite equal starting weights, females ate less but gained more weight on HFD compared to males. Blood glucose did not increase is females compared to controls but increased in males (12 vs 20 mmol/L). Initial (2-kidney) GFR was 1,6x higher females compared to males (554±73 vs 371±64 uL/min) and 1,5x after UNX. GFR in the females dropped towards the males GFR 4 weeks after diet initiation. UACR increased from 600 ug/mg towards 41200 ug/mg in all groups. BUN was highest in males on 100 mg/L LNNA (40 mg/dL) followed by males on 50 mg/L LNNA (28 mg/dL) and females on 100 mg/L LNNA (23 mg/dL). Kidneys of males (50 mg/L LNNA) were significant heavier the females (100 mg/L LNNA). Pathology showed extensive glomerular and mild tubular damage with arteriolar hyalinosis in males (50 and 100 mg/L LNNA). Females showed moderate glomerular damage and very mild tubular damage with sporadic arteriolar hyalinosis

Conclusion

Males and females respond different to a diabetes-inducing diet. Females has larger initial kidney function, comparable UACR, lower BUN and lower kidney weight and showed less renal damage compared to male mice. Despite the same dietary induction, females stayed metabolic healthy whereas males developed more pronounced diabetes and kidney damage. This is in accordance with clinical data and indicates the need for adjusted treatment guidelines for men and woman.

Funding

  • Commercial Support