title: Synergistic induction of osteopontin by aldosterone and inflammatory cytokines in mesangial cells.
abstract: Hypertensive nephrosclerosis is characterized by activation of the renin-angiotensin-aldosterone system in combination with an inflammatory response characterized by an infiltration of T-cells and mononuclear cells, which release proinflammatory cytokines like IL-1beta/TNFalpha. In various models of experimental hypertensive disease the chemokine osteopontin (OPN) enhances further leukocyte infiltration. Therefore, we investigated the induction of OPN expression in renal mesangial cells (MCs) by aldosterone and the inflammatory cytokines IL-1beta/TNFalpha. Incubation with aldosterone resulted in a time- and concentration-dependent increase in OPN mRNA and protein. OPN mRNA expression followed a biphasic time course with an early increase between 4 and 8 h and the second phase starting at 14 h. The early phase was independent of protein synthesis, indicating a direct effect of aldosterone. Aldosterone-mediated induction of OPN was prevented by spironolactone, indicative of a receptor-mediated aldosterone effect. The mineralocorticoid receptor (MR) was identified in MCs by RT-PCR and immunoprecipitation, and shown to interact with a putative aldosterone-response element of the OPN promoter. The proinflammatory cytokines IL-1beta and TNFalpha only marginally affected OPN expression in MCs. However, coincubation of aldosterone and the cytokines synergistically increased OPN mRNA and protein levels. Since the synergistic effect on OPN mRNA was inhibited by diphenyleneiodonium, we assume an involvement of reactive oxygen species (ROS). We conclude that the chemokine OPN is a target gene of aldosterone in renal MCs, which is activated via the MR, and that proinflammatory cytokines enhance aldosterone-dependent OPN expression. In vivo, this may result in further leukocyte infiltration aggravating hypertensive nephrosclerosis.
authors.affiliation: Department of Nephrology, Medical Clinic III, University of Frankfurt/Main, Germany. gauer@em.uni-frankfurt.de
authors.forename: Stefan
authors.initials: S
authors.lastname: Gauer
authors.forename: Ingeborg A
authors.initials: IA
authors.lastname: Hauser
authors.forename: Nicholas
authors.initials: N
authors.lastname: Obermüller
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Holzmann
authors.forename: Helmut
authors.initials: H
authors.lastname: Geiger
authors.forename: Margarete
authors.initials: M
authors.lastname: Goppelt-Struebe
mesh_terms: D000450:Aldosterone / Q000494:pharmacology* / Q000502:physiology; D000818:Animals; D002634:Chemotaxis, Leukocyte; D004357:Drug Synergism; D006973:Hypertension / Q000150:complications; D053583:Interleukin-1beta / Q000494:pharmacology*; D050527:Mesangial Cells / Q000187:drug effects* / Q000378:metabolism; D009400:Nephrosclerosis / Q000209:etiology / Q000503:physiopathology; D009861:Onium Compounds / Q000494:pharmacology; D053495:Osteopontin / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D018161:Receptors, Mineralocorticoid / Q000187:drug effects / Q000502:physiology; D012084:Renin-Angiotensin System / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
chemical_list: D053583:Interleukin-1beta; D009861:Onium Compounds; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D018161:Receptors, Mineralocorticoid; C506897:Spp1 protein, rat; D014409:Tumor Necrosis Factor-alpha; D053495:Osteopontin; D000450:Aldosterone; C007517:diphenyleneiodonium