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

Kidney Int. 2016 May;89(5):1075-1089. doi: 10.1016/j.kint.2016.01.027. Epub 2016 Mar 29.


Hepatocyte nuclear factor 1α (HNF1α) is a transcription factor expressed in the liver, pancreas, and proximal tubule of the kidney. Mutations of HNF1α cause an autosomal dominant form of diabetes mellitus (MODY-HNF1A) and tubular dysfunction. To gain insights into the role of HNF1α 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 β2-microglobulin, indicating a major endocytic defect due to decreased expression of megalin/cubilin receptors. We identified several binding sites for HNF1α in promoters of Lrp2 and Cubn genes encoding megalin and cubilin, respectively. The functional interaction of HNF1α with these promoters was shown in C33 epithelial cells lacking endogenous HNF1α. 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 HNF1α. Transfection of human proximal tubule HK2 cells with HNF1α 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, HNF1α 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.

Keywords: diabetes insipidus; endocytosis; proximal tubule; transcription regulation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Animals
  • Binding Sites
  • Case-Control Studies
  • Cells, Cultured
  • Diabetes Mellitus, Type 2 / genetics*
  • Diabetes Mellitus, Type 2 / metabolism
  • Diabetes Mellitus, Type 2 / physiopathology
  • Diabetic Nephropathies / genetics*
  • Diabetic Nephropathies / metabolism
  • Diabetic Nephropathies / physiopathology
  • Endocytosis*
  • Female
  • Gene Expression Regulation
  • Genetic Predisposition to Disease
  • Hepatocyte Nuclear Factor 1-alpha / deficiency
  • Hepatocyte Nuclear Factor 1-alpha / genetics*
  • Hepatocyte Nuclear Factor 1-alpha / metabolism
  • Humans
  • Kidney Tubules, Proximal / metabolism*
  • Kidney Tubules, Proximal / physiopathology
  • Low Density Lipoprotein Receptor-Related Protein-2 / genetics
  • Low Density Lipoprotein Receptor-Related Protein-2 / metabolism
  • Male
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Middle Aged
  • Mutation*
  • Phenotype
  • Promoter Regions, Genetic
  • Proteinuria / genetics*
  • Proteinuria / metabolism
  • Proteinuria / physiopathology
  • Receptors, Cell Surface / genetics
  • Receptors, Cell Surface / metabolism
  • Signal Transduction
  • Transfection
  • Young Adult


  • HNF1A protein, human
  • Hepatocyte Nuclear Factor 1-alpha
  • Hnf1a protein, mouse
  • LRP2 protein, human
  • Low Density Lipoprotein Receptor-Related Protein-2
  • Lrp2 protein, mouse
  • Receptors, Cell Surface
  • intrinsic factor-cobalamin receptor

Supplementary concepts

  • Maturity-Onset Diabetes of the Young, Type 3