title: Suppressors of cytokine signaling regulate angiotensin II-activated Janus kinase-signal transducers and activators of transcription pathway in renal cells.
abstract: Suppressors of cytokine signaling (SOCS) family is constituted by cytokine-inducible proteins that modulate receptor signal transduction via tyrosine kinases, mainly the Janus kinase-signal transducers and activators of transcription (JAK-STAT) pathway. Differential SOCS expression was noted in renal cells that were incubated with inflammatory stimuli, but the role of SOCS in the pathogenesis of renal diseases is not yet well defined. Because angiotensin II (Ang II) plays a key role in renal disease, SOCS proteins were studied as a novel mechanism involved in the negative regulation of Ang II-mediated processes. Systemic Ang II infusion for 3 d increased the renal mRNA expression of SOCS-3 and SOCS-1. SOCS protein synthesis was found in glomerular mesangial area and tubules. In cultured mesangial cells and tubular epithelial cells, Ang II induced a rapid and transient SOCS-3 and SOCS-1 expression in parallel with JAK2 and STAT1 activation. In both cell types, overexpression of SOCS proteins prevented the STAT activation in response to Ang II. SOCS expression observed in Ang II-infused rats and in Ang II-stimulated cells was significantly inhibited by treatment with AT(1) but not AT(2) receptor antagonist and was attenuated in mesangial cells from AT(1a)-deficient mice, demonstrating the implication of AT(1) in those responses. In SOCS-3 knockdown studies, antisense oligonucleotides inhibited the expression of SOCS-3 and increased the Ang II-induced STAT activation and c-Fos/c-Jun expression, then resulting in a more severe renal damage. These results suggest that SOCS proteins may act as negative regulators of Ang II signaling in renal cells and implicate SOCS as important modulators of renal damage.
authors.affiliation: Renal and Vascular Research Laboratory, Fundación Jiménez Díaz, Autonoma University, Avda Reyes Católicos 2, Madrid, Spain 28040. cgomez@fjd.es
authors.forename: Purificación
authors.initials: P
authors.lastname: Hernández-Vargas
authors.forename: Oscar
authors.initials: O
authors.lastname: López-Franco
authors.forename: Guillermo
authors.initials: G
authors.lastname: Sanjuán
authors.forename: Mónica
authors.initials: M
authors.lastname: Rupérez
authors.forename: Guadalupe
authors.initials: G
authors.lastname: Ortiz-Muñoz
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Suzuki
authors.forename: Pablo
authors.initials: P
authors.lastname: Aguado-Roncero
authors.forename: Gloria
authors.initials: G
authors.lastname: Pérez-Tejerizo
authors.forename: Julia
authors.initials: J
authors.lastname: Blanco
authors.forename: Jesús
authors.initials: J
authors.lastname: Egido
authors.forename: Marta
authors.initials: M
authors.lastname: Ruiz-Ortega
authors.forename: Carmen
authors.initials: C
authors.lastname: Gómez-Guerrero
mesh_terms: D000804:Angiotensin II / Q000378:metabolism*; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000818:Animals; D002478:Cells, Cultured; D016207:Cytokines / Q000037:antagonists & inhibitors; D004268:DNA-Binding Proteins / Q000502:physiology*; D004847:Epithelial Cells / Q000187:drug effects; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000502:physiology*; D053614:Janus Kinase 2; D007668:Kidney / Q000187:drug effects*; D019808:Losartan / Q000494:pharmacology; D051379:Mice; D011505:Protein-Tyrosine Kinases / Q000502:physiology*; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D051381:Rats; D012097:Repressor Proteins / Q000502:physiology; D050794:STAT1 Transcription Factor; D015398:Signal Transduction / Q000187:drug effects; D015534:Trans-Activators / Q000502:physiology*; D014157:Transcription Factors / Q000502:physiology; D015533:Transcriptional Activation / Q000187:drug effects
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D016207:Cytokines; D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; D011518:Proto-Oncogene Proteins; D012097:Repressor Proteins; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; C494080:Stat1 protein, mouse; C494081:Stat1 protein, rat; D015534:Trans-Activators; D014157:Transcription Factors; D000804:Angiotensin II; D011505:Protein-Tyrosine Kinases; C507924:JAK2 protein, human; C507926:Jak2 protein, mouse; C507927:Jak2 protein, rat; D053614:Janus Kinase 2; D019808:Losartan