Hum, Julia M.O’Bryan, Linda M.Tatiparthi, Arun K.Clinkenbeard, Erica L.Ni, PuCramer, Martin S.Bhaskaran, ManojJohnson, Robert L.Wilson, Jonathan M.Smith, Rosamund C.White, Kenneth E.2020-06-222020-06-222019-04-01Hum, J. M., O'Bryan, L. M., Tatiparthi, A. K., Clinkenbeard, E. L., Ni, P., Cramer, M. S., Bhaskaran, M., Johnson, R. L., Wilson, J. M., Smith, R. C., & White, K. E. (2019). Sustained Klotho delivery reduces serum phosphate in a model of diabetic nephropathy. Journal of applied physiology (Bethesda, Md. : 1985), 126(4), 854–862. https://doi.org/10.1152/japplphysiol.00838.2018https://hdl.handle.net/1805/23034Diabetic nephropathy (DN) is a primary cause of end-stage renal disease and is becoming more prevalent because of the global rise in type 2 diabetes. A model of DN, the db/db uninephrectomized (db/db-uni) mouse, is characterized by obesity, as well as compromised renal function. This model also manifests defects in mineral metabolism common in DN, including hyperphosphatemia, which leads to severe endocrine disease. The FGF23 coreceptor, α-Klotho, circulates as a soluble, cleaved form (cKL) and may directly influence phosphate handling. Our study sought to test the effects of cKL on mineral metabolism in db/db-uni mice. Mice were placed into either mild or moderate disease groups on the basis of the albumin-to-creatinine ratio (ACR). Body weights of db/db-uni mice were significantly greater across the study compared with lean controls regardless of disease severity. Adeno-associated cKL administration was associated with increased serum Klotho, intact, bioactive FGF23 (iFGF23), and COOH-terminal fragments of FGF23 (P < 0.05). Blood urea nitrogen was improved after cKL administration, and cKL corrected hyperphosphatemia in the high- and low-ACR db/db-uni groups. Interestingly, 2 wk after cKL delivery, blood glucose levels were significantly reduced in db/db-uni mice with high ACR (P < 0.05). Interestingly, several genes associated with stabilizing active iFGF23 were also increased in the osteoblastic UMR-106 cell line with cKL treatment. In summary, delivery of cKL to a model of DN normalized blood phosphate levels regardless of disease severity, supporting the concept that targeting cKL-affected pathways could provide future therapeutic avenues in DN.en-USPublisher PolicycKLDiabetesFGF23KlothoPhosphateArticle