Ablation of the Renal Urea Transporters UT‐A1 and UT‐A3 Replicates the Benefits of a Low‐protein Diet in Attenuating Diabetic Nephropathy

Diabetic nephropathy (DN) is a leading cause of kidney failure worldwide. Progression of DN can be slowed with a low‐protein diet; however, Western diets exceed the amount of protein physiologically needed, thus excess urea is generated and excreted by the kidney. Urea is reabsorbed in the inner medulla by the urea transporters UT‐A1 and UT‐A3. Although regulation of urea handling by these transporters controls urine concentration, the impact of these transporters on DN has not been explored. We induced DN in wild type (WT) and UT‐A1/A3 null mice (KO) using low‐dose streptozotocin injections and fed the mice a low (LP; 14%)‐, normal (NP; 25%)‐ or high (HP; 40%)‐protein diet over 10 wk. All DN mice demonstrated glycosuria and polyuria regardless of diet or genotype. Creatinine clearance was dampened in DN WT mice on LP and NP diets and was significantly decreased in DN WT mice on a HP diet. Interestingly, DN KO mice did not have diminished creatinine clearance rates regardless of diet suggesting the inability to reabsorb urea preserves renal function in DN. Histological analysis showed advanced interstitial fibrosis in WT DN mice fed a NP and HP diet; however, diabetic KO mice on the same diets had minimal fibrosis. Both DN and high urea levels are associated oxidative stress, prompting us to investigate multiple markers of oxidative stress. We found that DN KO mice fed HP diet were protected from the oxidative stress observed in DN WT mice on the same diet. Our data indicate in the absence of UT‐A1 and UT‐A3, the collecting duct fails to reabsorb the excess urea from a high protein diet and in doing so, prevents the interstitial fibrosis that occurs as a consequence of increased oxidative stress in the diabetic kidney. Support or Funding Information HHMI Science Education Program Award #52006923