In order to study mechanisms of renal fibrosis, ADTKD-UMOD and ER stress due to uromodulin mutations relevant to ADTKD-UMOD in humans, we generated a targeted mouse knock-in model by homologous recombination in mouse embryonic stem (ES) cells, to produce mice carrying a known disease-causing mutation, Cys125Arg (C125R), within the mouse Umod gene. Here, UMOD is linked to autosomal dominant medullary cystic kidney disease with or without hyperuricemia.