Hyperlipidemia-associated renal damage decreases Klotho expression in kidneys from ApoE knockout mice

PLoS One. 2013 Dec 30;8(12):e83713. doi: 10.1371/journal.pone.0083713. eCollection 2013.

Abstract

Background: Klotho is a renal protein with anti-aging properties that is downregulated in conditions related to kidney injury. Hyperlipidemia accelerates the progression of renal damage, but the mechanisms of the deleterious effects of hyperlipidemia remain unclear.

Methods: We evaluated whether hyperlipidemia modulates Klotho expression in kidneys from C57BL/6 and hyperlipidemic apolipoprotein E knockout (ApoE KO) mice fed with a normal chow diet (ND) or a Western-type high cholesterol-fat diet (HC) for 5 to 10 weeks, respectively.

Results: In ApoE KO mice, the HC diet increased serum and renal cholesterol levels, kidney injury severity, kidney macrophage infiltration and inflammatory chemokine expression. A significant reduction in Klotho mRNA and protein expression was observed in kidneys from hypercholesteromic ApoE KO mice fed a HC diet as compared with controls, both at 5 and 10 weeks. In order to study the mechanism involved in Klotho down-regulation, murine tubular epithelial cells were treated with ox-LDL. Oxidized-LDL were effectively uptaken by tubular cells and decreased both Klotho mRNA and protein expression in a time- and dose-dependent manner in these cells. Finally, NF-κB and ERK inhibitors prevented ox-LDL-induced Klotho downregulation.

Conclusion: Our results suggest that hyperlipidemia-associated kidney injury decreases renal expression of Klotho. Therefore, Klotho could be a key element explaining the relationship between hyperlipidemia and aging with renal disease.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apolipoproteins E / deficiency*
  • Apolipoproteins E / genetics
  • Cell Line
  • Cells, Cultured
  • Cytokines / metabolism
  • Disease Models, Animal
  • Gene Expression Regulation
  • Gene Expression*
  • Glucuronidase / genetics*
  • Glucuronidase / metabolism
  • Hyperlipidemias / complications*
  • Hyperlipidemias / genetics*
  • Inflammation / etiology
  • Inflammation / pathology
  • Inflammation Mediators / metabolism
  • Kidney / metabolism
  • Kidney / pathology
  • Kidney Diseases / etiology*
  • Lipid Metabolism
  • Lipoproteins, LDL / metabolism
  • Male
  • Mice
  • Mice, Knockout
  • Oxidative Stress

Substances

  • Apolipoproteins E
  • Cytokines
  • Inflammation Mediators
  • Lipoproteins, LDL
  • oxidized low density lipoprotein
  • Glucuronidase
  • klotho protein

Grant support

This work has been supported by grants from FIS (Programa Miguel Servet: CP10/00479) to JAM and ISCIII (Programa de Estabilización) and PI10/00234 to LMBC. Fundación Conchita Rábago to CS and ARN. Ministry of Science (SAF2012/38830) and Sociedad Española de Nefrologia to CGG. ISCIII and FEDER funds PS09/00447, Sociedad Española de Nefrologia, ISCIII-RETIC REDinREN/RD06/0016, Comunidad de Madrid/CIFRA/S2010/BMD-2378 to AO, and ISCIII-Redes RECAVA (RD06/0014/0035) REDINREN (RD12/0021/), European Network (HEALTH F2-2008-200647), Euro Salud EUS2005-03565, cvREMOD, Fundacion Lilly, FRIAT and ISCIII fund PI10/00072 to JE. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.