Abstract
CLCF-1 is a cytokine known for B-cell stimulation and for neurotrophic properties. We have identified CLCF-1 as a potential injurious factor in the human renal disease focal segmental glomerulosclerosis (FSGS). We investigated its effects on renal cells and renal function in in vitro and in vivo studies. Methods include measurement of the effect of CLCF-1 on phosphorylation of target molecules of the JAK/STAT pathway, on cytoskeleton and cell morphology in cultured podocytes, on albumin permeability of isolated rat glomeruli, and on tissue phosphorylation and urine albumin after acute or chronic CLCF-1 injection. In addition, cell sorting was performed to determine the presence of cells expressing CLCF-1 in spleen and bone marrow of normal mice and the effect of CLCF-1 infusion on splenic B-cell populations. CLCF-1 increased phosphorylation of STAT3 in multiple cell types, activated podocytes leading to formation of lamellipodia and decrease in basal stress fibers, increased glomerular albumin permeability, and increased STAT3 phosphorylation of peripheral blood cells and renal cortex. CLCF-1 increased urine albumin/creatinine ratio in mice and increased B-cell expression of IgG in mouse spleen. We conclude that CLCF-1 has potentially important systemic effects, alters podocyte function, and may contribute to renal dysfunction and albuminuria.
Highlights
CLCF-1 was originally described in 1999 by subtractive hybridization using a cDNA library constructed from activated Jurkat lymphoma cells [1, 2]
We have found that JAK2 and STAT3 are the predominant isoforms in glomeruli and podocytes of mice and rats
CLCF-1 is expressed in cells of bone marrow and peripheral blood as well as other tissues
Summary
CLCF-1 was originally described in 1999 by subtractive hybridization using a cDNA library constructed from activated Jurkat lymphoma cells [1, 2]. It was found to have neurotrophic activity and was termed neurotropin-1/B-cellstimulating factor-3 (NNT-1/BSF-3) [2]. It is expressed in lymph nodes and spleen, bone marrow, peripheral blood lymphocytes, ovary, placenta, kidney, pituitary, fetal liver, and other tissues [3]. It can be actively secreted from cells with heteromeric partners including cytokine receptor-like factor-1 (CRLF-1) and soluble ciliary neurotrophic factor receptor α (sCNTFRα) [4, 5]. There have been no reports that implicate either of CLCF-1 or CRLF-1 in initiating injury or causing disease
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