Tubular proteinuria in patients with HNF1α mutations: HNF1α drives endocytosis in the proximal tubule

摘要: Hepatocyte nuclear factor 1α (HNF1α) is a transcription expressed in the liver, pancreas, and proximal tubule of kidney. Mutations HNF1α cause an autosomal dominant form diabetes mellitus (MODY-HNF1A) tubular dysfunction. To gain insights into role tubule, we analyzed Hnf1a- deficient mice. Compared with wild-type littermates, Hnf1a knockout mice showed low-molecular-weight proteinuria 70% decrease uptake β 2 -microglobulin, indicating major endocytic defect due to decreased expression megalin/cubilin receptors. We identified several binding sites for promoters Lrp2 Cubn genes encoding megalin cubilin, respectively. The functional interaction these was shown C33 epithelial cells lacking endogenous HNF1α. Defective receptor-mediated endocytosis confirmed from could be rescued by transfection but not mutant Transfection human HK2 able upregulate cubilin increase albumin. Low-molecular-weight consistently detected individuals HNF1A mutations compared healthy controls patients non–MODY-HNF1A mellitus. Thus, plays key constitutive hence regulating These findings provide new insight renal phenotype .