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.

Creator(s)

Mukut Sharma
Jianping Zhou
Jean-François Gauchat
Ram Sharma
Ellen T. McCarthy
Tarak Srivastava, Children's Mercy HospitalFollow
Virginia J. Savin

Document Type

Article

Publication Date

10-1-2015

Identifier

PMCID: PMC4569535 DOI: 10.1016/j.trsl.2015.03.002

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.

Journal Title

Transl Res

Volume

166

Issue

4

First Page

384

Last Page

398

MeSH Keywords

Albumins; Animals; Antibodies, Blocking; Cytokines; Glomerular Filtration Barrier; Glomerulosclerosis, Focal Segmental; Humans; Janus Kinase 2; Kidney Glomerulus; Male; Permeability; Phosphorylation; Protein Kinase Inhibitors; Protein Multimerization; Rats, Sprague-Dawley; Receptors, Cytokine; STAT3 Transcription Factor; Up-Regulation

Comments

Grant support

• DK R21 00292588/DK/NIDDK NIH HHS/United States

• I01 BX001037/BX/BLRD VA/United States

• R21 DK081148/DK/NIDDK NIH HHS/United States

• R01 DK064969/DK/NIDDK NIH HHS/United States

• R01 DK43752/DK/NIDDK NIH HHS/United States

• 1R01 DK064969/DK/NIDDK NIH HHS/United States

Recommended Citation

Sharma M, Zhou J, Gauchat JF, et al. 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. Transl Res. 2015;166(4):384-398. doi:10.1016/j.trsl.2015.03.002