title: Suppressors of cytokine signaling abrogate diabetic nephropathy.
abstract: Activation of Janus kinase/signal transducers and activators of transcription (JAK/STAT) is an important mechanism by which hyperglycemia contributes to renal damage, suggesting that modulation of this pathway may prevent renal and vascular complications of diabetes. Here, we investigated the involvement of suppressors of cytokine signaling (SOCS) as intracellular negative regulators of JAK/STAT activation in diabetic nephropathy. In a rat model, inducing diabetes resulted in JAK/STAT activation and increased expression of SOCS1 and SOCS3. In humans, we observed increased expression of glomerular and tubulointerstitial SOCS proteins in biopsies of patients with diabetic nephropathy. In vitro, high concentrations of glucose activated JAK/STAT/SOCS in human mesangial and tubular cells. Overexpression of SOCS reversed the glucose-induced activation of the JAK/STAT pathway, expression of STAT-dependent genes (chemokines, growth factors, and extracellular matrix proteins), and cell proliferation. In vivo, intrarenal delivery of adenovirus expressing SOCS1 and SOCS3 to diabetic rats significantly improved renal function and reduced renal lesions associated with diabetes, such as mesangial expansion, fibrosis, and influx of macrophages. SOCS gene delivery also decreased the activation of STAT1 and STAT3 and the expression of proinflammatory and profibrotic proteins in the diabetic kidney. In summary, these results provide direct evidence for a link between the JAK/STAT/SOCS axis and hyperglycemia-induced cell responses in the kidney. Suppression of the JAK/STAT pathway by increasing intracellular SOCS proteins may have therapeutic potential in diabetic nephropathy.
authors.affiliation: Renal and Vascular Research Laboratory, Fundacion Jimenez Diaz, Autonoma University, Madrid, Spain.
authors.forename: Guadalupe
authors.initials: G
authors.lastname: Ortiz-Muñoz
authors.forename: Virginia
authors.initials: V
authors.lastname: Lopez-Parra
authors.forename: Oscar
authors.initials: O
authors.lastname: Lopez-Franco
authors.forename: Paula
authors.initials: P
authors.lastname: Fernandez-Vizarra
authors.forename: Beñat
authors.initials: B
authors.lastname: Mallavia
authors.forename: Claudio
authors.initials: C
authors.lastname: Flores
authors.forename: Ana
authors.initials: A
authors.lastname: Sanz
authors.forename: Julia
authors.initials: J
authors.lastname: Blanco
authors.forename: Sergio
authors.initials: S
authors.lastname: Mezzano
authors.forename: Alberto
authors.initials: A
authors.lastname: Ortiz
authors.forename: Jesus
authors.initials: J
authors.lastname: Egido
authors.forename: Carmen
authors.initials: C
authors.lastname: Gomez-Guerrero
mesh_terms: D000256:Adenoviridae; D000368:Aged; D000818:Animals; D016022:Case-Control Studies; D002460:Cell Line; D049109:Cell Proliferation; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism / Q000628:therapy; D003928:Diabetic Nephropathies / Q000378:metabolism* / Q000628:therapy; D005786:Gene Expression Regulation; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D006801:Humans; D006943:Hyperglycemia / Q000378:metabolism*; D053612:Janus Kinases / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D051381:Rats; D017208:Rats, Wistar; D050791:STAT Transcription Factors / Q000378:metabolism*; D050826:Suppressor of Cytokine Signaling Proteins / Q000378:metabolism*
chemical_list: D050791:STAT Transcription Factors; D050826:Suppressor of Cytokine Signaling Proteins; D053612:Janus Kinases