Abstract: TH-PO701

Absence of Inner Medullary Urea Transporters Attenuates Fibrosis in Diabetic Nephropathy

Session Information

Category: Diabetes

  • 501 Diabetes Mellitus and Obesity: Basic - Experimental

Authors

  • Rianto, Fitra, Emory University School of Medicine, Atlanta, Georgia, United States
  • Blount, Mitsi A., Emory University School of Medicine, Atlanta, Georgia, United States
  • Hasounah, Faten, Emory University, Atlanta, Georgia, United States
  • Ruiz, Joseph Antonio, Emory University, Atlanta, Georgia, United States
  • Sands, Jeff M., Emory University Renal Division, Atlanta, Georgia, United States
  • Klein, Janet D., Emory University, Atlanta, Georgia, United States
Background

Kidney fibrosis is commonly observed in diabetic nephropathy. Animal studies show that a low protein diet reduces the incidence of diabetic nephropathy and kidney fibrosis, suggesting that kidney urea levels may contribute to nephropathy. Benefits of low protein diets in patients are controversial. We investigated diabetes (DM)-related kidney fibrosis under conditions of minimal urea reabsorption and maximal urea load.

Methods

C57Bl6 mice +/- genetic ablation of UT-A1 and UT-A3 urea transporters (A1/A3 KO mice) were given daily doses of streptozotocin (55mg/kg/day) until blood glucose >200mg/dl. After 4 weeks mice were given low (14%) or high (40%) protein diets for 2 weeks (group 1) or 5 weeks (group 2). Kidneys were collected for protein and histochemical analysis.

Results

Mice required between 4 to 7 days injection of STZ to produce blood glucose levels >200 mg/dl. Body weights of non-DM mice remained stable while DM WT mice lost ~2% and A1/A3 KO mice lost ~14% body weight prior to termination. Urine values for 40%-fed DM mice: urine urea: 2.5±03 mmol/Uv WT vs 2.9±0.3 mmol/Uv KO; in mEq/L: Na: 147±6.8 WT /132±2.2 KO; Cl: 102±0.7 WT/97±0.7 KO; K: 6.3±0.5 WT/5.8±0.8 KO. Urine volume in both WT and UT-A1/A3 mice was increased by diabetes, but UT-A1/A3 KO mice still produced more urine than WT. Smooth muscle actin (SMA), vimentin were used as markers of fibrosis. In the 2 week high protein fed mice, diabetic WT mice showed 56% increased SMA vs diabetic WT mice fed a 14% protein diet whereas the A1/A3 KO mice showed a 26% increase with 40% protein feeding. Vimentin was 70% increased in high protein fed animals vs 12% increase in comparably fed A1/A3 KO mice. Trichrome staining of histological sections revealed higher collagen levels in 40%-fed WT mice vs A1/A3 KO mice.

Conclusion

These data show that fibrosis that characterizes diabetic nephropathy is attenuated by the absence of urea transporters. This suggests that urea reabsorption mediated by urea transporters in the inner medulla contributes to the development of diabetic renal fibrosis and is aggravated by high protein diet. If urea transport inhibitors replicate the effects of genetic knock out, they may represent a promising future therapy.

Funding

  • Private Foundation Support