Tubular proteinuria in patients with HNF1a mutations: HNF1a drives endocytosis in the proximal tubule.
Hepatocyte nuclear factor 1a (HNF1a) is a transcription factor expressed in the liver, pancreas, and proximal tubule of the kidney. Mutations of HNF1a cause an autosomal dominant form of diabetes mellitus (MODY HNF1A) and tubular dysfunction. To gain insights into the role of HNF1a in the proximal tubule, we analyzed Hnf1a deficient mice. Compared with wild type littermates, Hnf1a knockout mice showed low molecular weight proteinuria and a 70% decrease in the uptake of b2 microglobulin, indicating a major endocytic defect due to decreased expression of megalin/cubilin receptors. We identified several binding sites for HNF1a in promoters of Lrp2 and Cubn genes encoding megalin and cubilin, respectively. The functional interaction of HNF1a with these promoters was shown in C33 epithelial cells lacking endogenous HNF1a. Defective receptor mediated endocytosis was confirmed in proximal tubule cells from these knockout mice and could be rescued by transfection of wild type but not mutant HNF1a. Transfection of human proximal tubule HK2 cells with HNF1a was able to upregulate megalin and cubilin expression and to increase endocytosis of albumin. Low molecular weight proteinuria was consistently detected in individuals with HNF1A mutations compared with healthy controls and patients with non MODY HNF1A diabetes mellitus. Thus, HNF1a plays a key role in the constitutive expression of megalin and cubilin, hence regulating endocytosis in the proximal tubule of the kidney. These findings provide new insight into the renal phenotype of individuals with mutations of HNF1A.
Kidney international