P224
THE LIM PROTEIN, HIC-5, REGULATES AN EXTRACELLULAR MATRIXDERIVED
TGF- INDEPENDENT PRO-SCLEROTIC FEEDBACK LOOP IN MESANGIAL
CELLS, IN VITRO AND IN EXPERIMENTAL DIABETIC
GLOMERULOSCLEROSIS
Hornigold, N¹, Johnson, T², Banks, R¹, Mooney, A³
¹CRUK Clinical Centre, St Jame’s University Hospital, Leeds, ²University of Sheffield,
³Renal Unit, St Jame’s University Hospital, Leeds
We have demonstrated that mesangial cell expression of the LIM protein Hic-5 is pivotal in
the progression of glomerulosclerosis. Its expression is increased in response to mesangial
cell attachment to collagen I, associated with an increased susceptibility to apoptosis both in
vitro and in experimental glomerulosclerosis. We have now studied whether this is a direct
matrix/mesangial cell effect or whether it is dependent on TGF- paracrine effects. Using
stable si-RNA knock-down rat mesangial cell lines, we now show that Hic-5 modulates the
sclerotic phenotype of mesangial cells, regulating -smooth muscle actin expression, collagen
I precursor transcription, and other protein expression associated with collagen I ligation.
Through studies of Smad-3 and Smad-7 signalling, we can show that Hic-5 regulates TGF-dependent mesangial cell signalling (eg apoptosis susceptibility, collagen I pre-cursor
expression), but TGF- does not influence Hic-5 signalling (RA 2009). Furthermore, in
experimental diabetic glomerulosclerosis in nephrectomised rats, treatment with
transglutaminase-2 inhibitor reduced collagen I deposition (an effect independent of TGF-
expression [JASN 2009]) was associated with reduced Hic-5 expression, -SMA expression,
less glomerulosclerosis and reduced apoptosis. These findings suggest there is in mesangial
cells a TGF--independent pro-sclerotic feedback loop dependent on matrix-derived signals
in which Hic-5 is a pivotal signalling protein. This suggests Hic-5 might represent an
important target in therapeutic strategies to reduce glomerulosclerosis.
This work was supported by KRUK and the Yorkshire Kidney Research Fund.
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