Abstract
Galectin-3 is a β-galactoside binding lectin with roles in diverse processes including proliferation, apoptosis, inflammation and fibrosis which are dependent on different domains of the molecule and subcellular distribution. Although galectin-3 is known to be upregulated in acute kidney injury, the relative importance of its different domains and functions are poorly understood in the underlying pathogenesis. Therefore we experimentally modulated galectin-3 in folic acid (FA)-induced acute kidney injury utilising modified citrus pectin (MCP), a derivative of pectin which can bind to the galectin-3 carbohydrate recognition domain thereby predominantly antagonising functions linked to this role. Mice were pre-treated with normal or 1% MCP-supplemented drinking water one week before FA injection. During the initial injury phase, all FA-treated mice lost weight whilst their kidneys enlarged secondary to the renal insult; these gross changes were significantly lessened in the MCP group but this was not associated with significant changes in galectin-3 expression. At a histological level, MCP clearly reduced renal cell proliferation but did not affect apoptosis. Later, during the recovery phase at two weeks, MCP-treated mice demonstrated reduced galectin-3 in association with decreased renal fibrosis, macrophages, pro-inflammatory cytokine expression and apoptosis. Other renal galectins, galectin-1 and -9, were unchanged. Our data indicates that MCP is protective in experimental nephropathy with modulation of early proliferation and later galectin-3 expression, apoptosis and fibrosis. This raises the possibility that MCP may be a novel strategy to reduce renal injury in the long term, perhaps via carbohydrate binding-related functions of galectin-3.
Highlights
Galectins are low molecular weight, calcium-independent, bgalactoside-binding lectins [1]
This expanded distribution was maintained in the recovery phase of folic acid (FA) nephropathy after 14 days and in addition galectin-3 positive cells were observed in fibrotic areas consistent with macrophage localisation (Figure 2C)
Administration of modified citrus pectin (MCP) (Group III) did not significantly alter galectin-3 mRNA levels at 2 days but there was a statistically significant reduction at day 14 (Figure 3A). This reduction was confirmed at the protein level at day 14: a galectin-3 doublet was detected at the expected size of around 30 kDa which was significantly decreased in FAanimals administered MCP (Figure 3D)
Summary
Galectins are low molecular weight, calcium-independent, bgalactoside-binding lectins [1]. Lower levels are sometimes observed in mature tubules [11] but the lectin is expressed in a more widespread distribution in models of acute kidney damage such as ischemia-reperfusion injury or high-dose folic acid (FA) treatment [12] In this latter model, FA initially undergoes glomerular filtration following systemic injection, and precipitates in the tubules which become damaged with a loss of epithelial cell integrity due to necrosis and apoptosis [13,14]. Several lines of evidence suggest that galectin-3 is beneficial in experimental kidney diseases such as polycystic kidney disease [18], nephrotoxic nephritis [19] and unilateral ureteric obstruction (UUO) [11], but its functional importance in FA-induced acute kidney injury is unknown We utilised this model and modulated galectin-3 levels using modified citrus pectin (MCP), a derivative of pectin; which is a soluble dietary fibre found in the peel and pulp of citrus fruits [20]. MCP contains fragments of the original pectin molecule, including rhamnogalacturonan 1 regions which contain galactan side-chains [21] which bind to the carbohydrate recognition domain of galectin-3 [22,23], modulating galectin-3 bioactivity by altering extracellular functions such as cell-cell interactions and inflammation
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