title: Janus kinase 2/signal transducer and activator of transcription 3 inhibitors attenuate the effect of cardiotrophin-like cytokine factor 1 and human focal segmental glomerulosclerosis serum on glomerular filtration barrier.
abstract: Recurrence of idiopathic focal segmental glomerulosclerosis (FSGS) after renal transplantation is believed to be caused by a circulating factor(s). We detected cardiotrophin-like cytokine factor 1 (CLCF1), a member of the interleukin 6 family, in the plasma from patients with recurrent FSGS. We hypothesized that CLCF1 contributes to the effect of FSGS serum on the glomerular filtration barrier in vitro. Presently, we studied the effect of CLCF1 on isolated rat glomeruli using an in vitro assay of albumin permeability (P(alb)). CLCF1 (0.05-100 ng/mL) increased P(alb) and caused maximal effect at 5-10 ng/mL (P < 0.001). The increase in Palb was analogous to the effect of FSGS serum. Anti-CLCF1 monoclonal antibody blocked the CLCF1-induced increase in P(alb) and significantly attenuated the effect of FSGS serum (P < 0.001). The heterodimer composed of CLCF1 and cosecreted molecule cytokine receptor-like factor 1 (CRLF1) attenuated the increase in P(alb) caused by CLCF1 or FSGS serum. Western blot analysis showed that CLCF1 upregulated phosphorylation of signal transducer and activator of transcription 3 (STAT3) (Tyr705) in glomeruli. This effect was diminished by the heterodimer CLCF1-CRLF1. Janus kinase 2 (JAK2) inhibitor BMS-1119543 or STAT3 inhibitor Stattic significantly blocked the effect of CLCF1 or FSGS serum on P(alb) (P < 0.001). These novel findings suggest that when monomeric CLCF1 increases P(alb), the heterodimer CLCF1-CRLF1 may protect the glomerular filtration barrier. We speculate that albuminuria in FSGS is related to qualitative or quantitative changes in the CLCF1-CRLF1 complex, and that JAK2 or STAT3 inhibitors may be novel therapeutic agents to treat FSGS.
authors.affiliation: Renal Research Laboratory, Research and Development, MBRF and Kansas City VA Medical Center, Kansas City, Mo; Kidney Institute, University of Kansas Medical Center, Kansas City, Kan. Electronic address: Mukut.sharma@va.gov.
authors.forename: Mukut
authors.initials: M
authors.lastname: Sharma
authors.affiliation: Renal Research Laboratory, Research and Development, MBRF and Kansas City VA Medical Center, Kansas City, Mo.
authors.forename: Jianping
authors.initials: J
authors.lastname: Zhou
authors.affiliation: Department of Pharmacology, University of Montreal, Montreal, Quebec, Canada.
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Gauchat
authors.affiliation: Renal Research Laboratory, Research and Development, MBRF and Kansas City VA Medical Center, Kansas City, Mo.
authors.forename: Ram
authors.initials: R
authors.lastname: Sharma
authors.affiliation: Kidney Institute, University of Kansas Medical Center, Kansas City, Kan.
authors.forename: Ellen T
authors.initials: ET
authors.lastname: McCarthy
authors.affiliation: Renal Research Laboratory, Research and Development, MBRF and Kansas City VA Medical Center, Kansas City, Mo; Section of Nephrology, Children's Mercy Hospital and University of Missouri at Kansas City, Kansas City, Mo.
authors.forename: Tarak
authors.initials: T
authors.lastname: Srivastava
authors.affiliation: Renal Research Laboratory, Research and Development, MBRF and Kansas City VA Medical Center, Kansas City, Mo; Kidney Institute, University of Kansas Medical Center, Kansas City, Kan.
authors.forename: Virginia J
authors.initials: VJ
authors.lastname: Savin
mesh_terms: D000418:Albumins / Q000378:metabolism; D000818:Animals; D019138:Antibodies, Blocking / Q000494:pharmacology; D016207:Cytokines / Q000494:pharmacology*; D060730:Glomerular Filtration Barrier / Q000187:drug effects / Q000378:metabolism*; D005923:Glomerulosclerosis, Focal Segmental / Q000097:blood*; D006801:Humans; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D007678:Kidney Glomerulus / Q000187:drug effects / Q000473:pathology; D008297:Male; D010539:Permeability / Q000187:drug effects; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D055503:Protein Multimerization / Q000187:drug effects; D017207:Rats, Sprague-Dawley; D018121:Receptors, Cytokine / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D000418:Albumins; D019138:Antibodies, Blocking; D016207:Cytokines; D047428:Protein Kinase Inhibitors; D018121:Receptors, Cytokine; D050796:STAT3 Transcription Factor; C121169:cardiotrophin-like cytokine; C113554:cytokine-like factor-1; D053614:Janus Kinase 2
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