CYP24A1 exacerbated activity during diabetes contributes to kidney tubular apoptosis via caspase-3 increased expression and activation

PLoS One. 2012;7(10):e48652. doi: 10.1371/journal.pone.0048652. Epub 2012 Oct 31.

Abstract

Decreases in circulating 25,hydroxyl-vitamin D3 (25 OH D3) and 1,25,dihydroxyl-vitamin D3 (1,25 (OH)2 D3) have been extensively documented in patients with type 2 diabetes. Nevertheless, the molecular reasons behind this drop, and whether it is a cause or an effect of disease progression is still poorly understood. With the skin and the liver, the kidney is one of the most important sites for vitamin D metabolism. Previous studies have also shown that CYP24A1 (an enzyme implicated in vitamin D metabolism), might play an important role in furthering the progression of kidney lesions during diabetic nephropathy. In this study we show a link between CYP24A1 increase and senescence followed by apoptosis induction in the renal proximal tubules of diabetic kidneys. We show that CYP24A1 expression was increased during diabetic nephropathy progression. This increase derived from protein kinase C activation and increased H(2)O(2) cellular production. CYP24A1 increase had a major impact on cellular phenotype, by pushing cells into senescence, and later into apoptosis. Our data suggest that control of CYP24A1 increase during diabetes has a beneficial effect on senescence induction and caspase-3 increased expression. We concluded that diabetes induces an increase in CYP24A1 expression, destabilizing vitamin D metabolism in the renal proximal tubules, leading to cellular instability and apoptosis, and thereby accelerating tubular injury progression during diabetic nephropathy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis*
  • Blotting, Western
  • Caspase 3 / genetics
  • Caspase 3 / metabolism*
  • Cells, Cultured
  • Diabetes Mellitus, Type 2 / blood
  • Diabetes Mellitus, Type 2 / genetics
  • Diabetes Mellitus, Type 2 / metabolism*
  • Diet, High-Fat
  • G1 Phase Cell Cycle Checkpoints / genetics
  • Gene Expression
  • Glucose / pharmacology
  • Humans
  • Hydrogen Peroxide / pharmacology
  • Kidney Tubules / drug effects
  • Kidney Tubules / metabolism*
  • Kidney Tubules / pathology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Oxidants / pharmacology
  • RNA Interference
  • Receptors, Calcitriol / genetics
  • Receptors, Calcitriol / metabolism
  • Receptors, Leptin / genetics
  • Receptors, Leptin / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • Steroid Hydroxylases / genetics
  • Steroid Hydroxylases / metabolism*
  • Up-Regulation / drug effects
  • Vitamin D3 24-Hydroxylase

Substances

  • Oxidants
  • Receptors, Calcitriol
  • Receptors, Leptin
  • Hydrogen Peroxide
  • Steroid Hydroxylases
  • CYP24A1 protein, human
  • Cyp24a1 protein, mouse
  • Vitamin D3 24-Hydroxylase
  • Caspase 3
  • Glucose

Grant support

The funds for this study were exclusively provided by starting funds from CR-HSCM (Centre de recherche- Hopital Sacré Coeur de Montréal, Montréal, QC, Canada). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.