Download KCa 3.1: A Potential Anti Fibrotic Target In IgA Nephropathy

KCa 3.1: A POTENTIAL ANTI FIBROTIC TARGET IN IgA
NEPHROPATHY
ABSTRACT
Introduction Chronic kidney disease (CKD) is a common condition worldwide. It is
known that fibrosis plays an important role in the progression of CKD to end stage
renal failure (ESRF). Despite much research, the mechanisms controlling renal
fibrosis are not fully understood. IgA nephropathy (IgAN) is a primary
glomerulonephritis characterised by the deposition of IgA1 containing immune
complexes in the mesangium leading to glomerular and tubulointerstitial fibrosis. A
direct effect of IgA1 on mesangial cells (MC), podocytes and proximal tubular
epithelial cells (PTEC) is believed to be crucial for the development of renal fibrosis
in IgAN. The intermediate-conductance Ca2+-activated potassium channel, KCa3.1,
has emerged as an important regulator of fibroblast proliferation in renal and other
diseases. The aim of this study was to investigate the expression of KCa3.1 in
cultured human MC, podocytes and PTEC and determine the effect of blocking
KCa3.1 on the in vitro response of human MC to IgA1.
Methods :. To determine whether human MC, podocytes and PTEC (hTERT cells)
constitutively express KCa3.1 cell lysates were subjected to western blotting. To
evaluate the role of KCa3.1 in the pro-inflammatory and pro-fibrotic response of
human MC to IgA1 serum starved human MC were incubated with increasing
concentrations of IgA1, with or without the KCa3.1 blocker, TRAM-34, for 24 hours.
KCa3.1 expression was measured by western blotting and changes in cytokine and
chemokine expression were measured using a bead-based multiplexing immunoassay
(Luminex).
Results: Human MC, podocytes and PTEC constitutively express KCa3.1. IgA1
induced an up-regulation of KCa3.1 expression in human MC and PTEC which could
be inhibited by the KCa3.1 blocker, TRAM-34, suggesting this effect was in part
mediated by KCa3.1 itself. Human MC exposed to IgA1, as expected, developed a
pro-inflammatory phenotype with secretion of IL-6. Administration of TRAM-34
inhibited the IgA1-mediated release of IL-6 by human MC.
Discussion: This is the first time KCa3.1 expression has been shown in human
podocytes. Expression of KCa3.1 by human MC, podocytes and PTEC, the
upregulation of KCa3.1 in human MC and PTEC by IgA1 and the inhibition of IgA1
induced human MC activation suggest a role for this Ca2+-activated potassium
channel in the glomerular and tubulointerstitial fibrosis characteristic of progressive
IgAN and may offer a novel therapeutic target in this common glomerular disease.