Megalin/LRP2 Expression is induced by peroxisome proliferator-activated receptor-alpha and –gamma: Physiopathological implications for kidney function

Kidney Int.

dc.creatorCabezas, Enrique
dc.creatorRamos, Bárbara
dc.creatorCéspedes, Carlos
dc.creatorVio, Carlos P.
dc.creatorBronfman, Miguel
dc.creatorMarzolo, María-Paz
dc.date2019-12-18T18:14:48Z
dc.date2022-07-07T22:04:07Z
dc.date2019-12-18T18:14:48Z
dc.date2022-07-07T22:04:07Z
dc.date2009
dc.date.accessioned2023-08-22T11:33:37Z
dc.date.available2023-08-22T11:33:37Z
dc.identifier13980001
dc.identifier13980001
dc.identifierhttps://hdl.handle.net/10533/237115
dc.identifier.urihttps://repositorioslatinoamericanos.uchile.cl/handle/2250/8344564
dc.descriptionBACKGROUND: Megalin is a large endocytic receptor with relevant functions during development and adult life. It is expressed at the apical surface of several epithelial cell types, including proximal tubule cells (PTCs) in the kidney, where it internalizes apolipoproteins, vitamins and hormones with their corresponding carrier proteins and signaling molecules. Despite the important physiological roles of megalin little is known about the regulation of its expression. By analyzing the human megalin promoter, we found three response elements for the peroxisomal proliferator-activated receptor (PPAR). The objective of this study was to test whether megalin expression is regulated by the PPARs. METHODOLOGY/PRINCIPAL FINDINGS: Treatment of epithelial cell lines with PPARα or PPARγ ligands increased megalin mRNA and protein expression. The stimulation of megalin mRNA expression was blocked by the addition of specific PPARα or PPARγ antagonists. Furthermore, PPAR bound to three PPAR response elements located in the megalin promoter, as shown by EMSA, and PPARα and its agonist activated a luciferase construct containing a portion of the megalin promoter and the first response element. Accordingly, the activation of PPARα and PPARγ enhanced megalin expression in mouse kidney. As previously observed, high concentrations of bovine serum albumin (BSA) decreased megalin in PTCs in vitro; however, PTCs pretreated with PPARα and PPARγ agonists avoided this BSA-mediated reduction of megalin expression. Finally, we found that megalin expression was significantly inhibited in the PTCs of rats that were injected with BSA to induce tubulointerstitial damage and proteinuria. Treatment of these rats with PPARγ agonists counteracted the reduction in megalin expression and the proteinuria induced by BSA. CONCLUSIONS: PPARα/γ and their agonists positively control megalin expression. This regulation could have an important impact on several megalin-mediated physiological processes and on pathophysiologies such as chronic kidney disease associated with diabetes and hypertension, in which megalin expression is impaired.
dc.descriptionFONDAP
dc.descriptionFONDAP
dc.languageeng
dc.relationinstname: Conicyt
dc.relationreponame: Repositorio Digital RI2.0
dc.relationinfo:eu-repo/grantAgreement/Fondap/13980001
dc.relationhttps://www.ncbi.nlm.nih.gov/pubmed/21311715
dc.rightsAtribución-NoComercial-SinDerivadas 3.0 Chile
dc.rightshttp://creativecommons.org/licenses/by-nc-nd/3.0/cl/
dc.rightsinfo:eu-repo/semantics/openAccess
dc.titleMegalin/LRP2 Expression is induced by peroxisome proliferator-activated receptor-alpha and –gamma: Physiopathological implications for kidney function
dc.titleKidney Int.
dc.typeArticulo
dc.typeinfo:eu-repo/semantics/article
dc.typeinfo:eu-repo/semantics/publishedVersion


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