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Suppressors of Cytokine Signaling Regulate Angiotensin II-Activated Janus Kinase-Signal Transducers and Activators of Transcription Pathway in Renal Cells

Purificación Hernández-Vargas^*, Oscar López-Franco^*, Guillermo Sanjuán^*, Mónica Rupérez^*, Guadalupe Ortiz-Muñoz^*, Yusuke Suzuki, Pablo Aguado-Roncero, Gloria Pérez-Tejerizo, Julia Blanco, Jesús Egido^*, Marta Ruiz-Ortega^* and Carmen Gómez-Guerrero^*

^* Renal and Vascular Research Laboratory, Pediatric Surgery Department, Fundación Jiménez Díaz, Autonoma University, Madrid, Spain; Division of Nephrology, Department of Internal Medicine, Juntendo University, Tokyo, Japan; and Department of Pathology, Hospital Clínico San Carlos, Madrid, Spain

Address correspondence to: Dr. Carmen Gómez-Guerrero, Renal and Vascular Research Laboratory, Fundación Jiménez Díaz, Avda Reyes Católicos 2, Madrid, Spain 28040. Phone: 34-91-5504800; Fax: 34-91-5442636; E-mail: cgomez{at}fjd.es

Received for publication May 11, 2004. Accepted for publication February 28, 2005.

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 AT₁ but not AT₂ receptor antagonist and was attenuated in mesangial cells from AT_1a-deficient mice, demonstrating the implication of AT₁ 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.

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Copyright © 2008 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673