title: Ablation of proximal tubular suppressor of cytokine signaling 3 enhances tubular cell cycling and modifies macrophage phenotype during acute kidney injury.
abstract: Suppressor of cytokine signaling 3 (SOCS-3) is an important intracellular negative regulator of several signaling pathways. We found that SOCS-3 is highly expressed in renal proximal tubules during acute kidney injury. To test the impact of this, conditional proximal tubular knockout mice (SOCS-3(sglt2Δ/sglt2Δ)) were created. These mice had better kidney function than their wild-type counterparts in aristolochic acid nephropathy and after ischemia/reperfusion injury. Kidneys of these knockout mice showed significantly more proximal tubular cell proliferation during the repair phase. A direct effect of SOCS-3 on tubular cell cycling was demonstrated by in vitro experiments showing a JAK/STAT pathway-dependent antimitotic effect of SOCS-3. Furthermore, acute damaged kidneys of the knockout mice contained increased numbers of F4/80(+) cells. Phenotypic analysis of these F4/80(+) cells indicated a polarization from classically activated to alternatively activated macrophages. In vitro, SOCS-3-overexpressing renal epithelial cells directly induced classical activation in cocultured macrophages, supporting the observed in vivo phenomenon. Thus, upregulation of SOCS-3 in stressed proximal tubules plays an important role during acute kidney injury by inhibition of reparative proliferation and by modulation of the macrophage phenotype. Antagonizing SOCS-3 could have therapeutic potential for acute kidney injury.
authors.affiliation: Department of Nephrology, Hannover Medical School, Hannover, Germany.
authors.forename: Nathan
authors.initials: N
authors.lastname: Susnik
authors.affiliation: Department of Nephrology, Hannover Medical School, Hannover, Germany.
authors.forename: Inga
authors.initials: I
authors.lastname: Sörensen-Zender
authors.affiliation: Department of Nephrology, Hannover Medical School, Hannover, Germany.
authors.forename: Song
authors.initials: S
authors.lastname: Rong
authors.affiliation: Department of Nephrology, Hannover Medical School, Hannover, Germany.
authors.forename: Sibylle
authors.initials: S
authors.lastname: von Vietinghoff
authors.affiliation: Department of Nephrology, Hannover Medical School, Hannover, Germany.
authors.forename: Xia
authors.initials: X
authors.lastname: Lu
authors.affiliation: LP2M, CNRS 3472, University of Nice-Sophia Antipolis, Nice, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Rubera
authors.affiliation: LP2M, CNRS 3472, University of Nice-Sophia Antipolis, Nice, France.
authors.forename: Michel
authors.initials: M
authors.lastname: Tauc
authors.affiliation: Institute of Transplant Immunology, Integrated Research and Treatment Center Transplantation, Hannover Medical School, Hannover, Germany.
authors.forename: Christine S
authors.initials: CS
authors.lastname: Falk
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, and Department of Medical Biology, The University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Warren S
authors.initials: WS
authors.lastname: Alexander
authors.affiliation: Division of Pediatric Nephrology, Gastroenterology and Metabolic Diseases, Children's Hospital, Hannover Medical School, Hannover, Germany.
authors.forename: Anette
authors.initials: A
authors.lastname: Melk
authors.affiliation: Department of Nephrology, Hannover Medical School, Hannover, Germany.
authors.forename: Herrmann
authors.initials: H
authors.lastname: Haller
authors.affiliation: Department of Nephrology, Hannover Medical School, Hannover, Germany.
authors.forename: Roland
authors.initials: R
authors.lastname: Schmitt
mesh_terms: D058186:Acute Kidney Injury / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D000818:Animals; D000943:Antigens, Differentiation / Q000378:metabolism; D049109:Cell Proliferation; D002478:Cells, Cultured; D018920:Coculture Techniques; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D005838:Genotype; D053612:Janus Kinases / Q000378:metabolism; D007687:Kidney Tubules, Proximal / Q000276:immunology / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D008262:Macrophage Activation; D008264:Macrophages / Q000276:immunology / Q000378:metabolism*; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010641:Phenotype; D034622:RNA Interference; D050791:STAT Transcription Factors / Q000378:metabolism; D015398:Signal Transduction; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000172:deficiency* / Q000235:genetics; D013997:Time Factors; D014162:Transfection
chemical_list: D000943:Antigens, Differentiation; D050791:STAT Transcription Factors; C491411:Socs3 protein, mouse; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; C036763:monocyte-macrophage differentiation antigen; D053612:Janus Kinases