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The Role Of Kca3.1 In IGA Nephropathy

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posted on 16.07.2019, 13:21 authored by Dina Nilasari
IgA nephropathy (IgAN) is the commonest pattern of primary glomerulonephritis worldwide, 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 thesis was to investigate the expression of KCa3.1 in cultured human MC, podocytes and PTEC and to determine the effect of blocking KCa3.1 on the in vitro response of human MC and PTEC to IgA1, and of PTEC to monomeric IgA1 (mIgA) and polymeric IgA1 (pIgA). Human MC, podocytes and PTEC were found to constitutively express KCa3.1. IgA1 induced an up-regulation of KCa3.1 synthesis by human MC and PTEC which could be inhibited by the KCa3.1 selective blockers, TRAM-34 and ICA- 17043, suggesting this effect was in part mediated by KCa3.1 itself. Human MC exposed to IgA1 developed a pro-inflammatory phenotype, with secretion of IL-6, which was inhibited by TRAM-34. The ability of KCa3.1 blockers to prevent IgA1 dependent changes in expression and synthesis of markers of fibrosis and epithelial mesenchymal transition (EMT) in PTECS suggests involvement of this potassium channel in tubulointerstitial damage in IgAN. In contrast with mIgA1, human serum pIgA1 induces human PTECs to increase protein synthesis and gene expression of KCa3.1, and markers of inflammation, EMT, and fibrosis (IL-6, TGF-b, GDF-15, PDGF-AA, a-SMA, FSP-1 and fibronectin). These results indicate the relationship between pIgA1 and KCa3.1 is pivotal to the mechanisms driving inflammation and fibrosis in the tubular interstitium. Controlling this relationship may prove critical in the search for a therapy to slow down renal damage in IgAN. The presence of KCa3.1 in the exosome fraction of media from hTERT/PTECS incubated with IgA1 and urine from IgAN patients suggests the possibility of using KCa3.1 as a marker for progression in IgAN. These studies provide evidence that KCa3.1 plays an important role in mesangial cell activation, EMT and ultimately extracellular matrix deposition and tubulointerstitial fibrosis in IgAN. The origin and role in IgAN pathogenesis of KCa3.1 in urinary exosomes requires further investigation.



Barratt, Barratt; Molyneux, Karen

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Department of Infection, Immunity and Inflammation

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University of Leicester

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