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

Cristina Sastre; Alfonso Rubio-Navarro; Irene Buendía; Carmen Gómez-Guerrero; Julia Blanco; Sebastian Mas; Jesús Egido; Luis Miguel Blanco-Colio; Alberto Ortiz; Juan Antonio Moreno

doi:10.1371/journal.pone.0083713

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.

Affiliations

¹ Vascular and Renal Research Lab, IIS-Fundación Jiménez Díaz, Autónoma University, Madrid, Spain.
² Hospital Clinico San Carlos, Madrid, Spain.
³ Vascular and Renal Research Lab, IIS-Fundación Jiménez Díaz, Autónoma University, Madrid, Spain ; Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM), Spain.

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*
Klotho Proteins
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 Proteins

Grants and funding

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.