Hyperlipidemia-associated renal damage decreases Klotho expression in kidneys from ApoE knockout mice Sastre, Cristina Rubio-Navarro, Alfonso Buendía, Irene Gomez-Guerrero, Carmen Blanco, Julia Mas, Sebastian Egido, Jesus Blanco-Colio, Luis Miguel Ortiz, Alberto Moreno, Juan Antonio 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. 2025-01-30T10:03:50Z 2025-01-30T10:03:50Z 2013-12-30 journal article Sastre C, Rubio-Navarro A, Buendía I, Gómez-Guerrero C, Blanco J, Mas S, Egido J, Blanco-Colio LM, Ortiz A, Moreno JA. 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. PMID: 24386260; PMCID: PMC3875485. https://hdl.handle.net/10481/101197 10.1371/journal.pone.0083713 eng http://creativecommons.org/licenses/by-nc-nd/4.0/ open access Attribution-NonCommercial-NoDerivatives 4.0 Internacional Public Library of Science