Advanced lipoxidation end‐products mediate lipid‐induced glomerular injury: role of receptor‐mediated mechanisms

Abstract

Atherosclerosis and renal disease are related conditions, sharing several risk factors. This includes hyperlipidaemia, which may result in enhanced lipoprotein accumulation and chemical modification, particularly oxidation, with formation of advanced lipoxidation endproducts (ALEs). We investigated whether increased lipid peroxidation plays a major role in the pathogenesis of lipid-induced renal disease, via receptor-mediated mechanisms involving the scavenger and advanced glycation endproduct (AGE) receptors. Mice knocked out for galectin-3 (Gal3(-/-)), an AGE receptor previously shown to protect from AGE-induced renal injury, and the corresponding wild-type (Gal3(+/+)) animals, were fed an atherogenic high-fat diet (HFD; 15% fat, 1.25% cholesterol and 0.5% sodium cholate); mice fed a normal-fat diet (NFD; 4% fat) served as controls. Gal3(+/+) mice fed a HFD developed glomerular disease, as indicated by proteinuria, mesangial expansion and glomerular hypertrophy and sclerosis. Glomerular injury was associated with increased glomerular matrix protein expression, ALE and oxidized LDL content, oxidative stress, AGE and scavenger receptor expression and macrophage infiltration, with only modest renal/glomerular fat accumulation and changes in lipid metabolism. Fibrotic and inflammatory changes, together with accumulation of ALEs, such as 4-hydroxy-2-nonenal adducts and N(epsilon)-carboxymethyllysine, oxidative stress and expression of the receptor of AGEs (RAGE), were significantly more marked in Gal3(-/-) animals, whereas fat deposition and abnormalities in lipid metabolism remained modest. Thus, lipid-induced renal damage is mainly dependent on lipid peroxidation with formation of carbonyl reactive species and ALEs, which accumulate within the kidney tissue, thus triggering receptor-mediated pro-inflammatory signalling pathways, as in atherogenesis. Moreover, galectin-3 exerts a significant role in the uptake and effective removal of modified lipoproteins, with diversion of these products from RAGE-dependent pro-inflammatory pathways associated with downregulation of RAGE expression.

Galectin-3 in diabetic patients

“…Moreover, both circulating and renal tissue levels of AGEs increased more markedly in response to diabetes and renal cortex RAGE expression was up-regulated even in control animals and increased in a significantly higher extent in diabetic mice. Similar features of more marked fibrosis and inflammation were observed in the aging [78], AGE-injection [79], and HFD [80] models.…”

“…In contrast with findings in the kidney and the aorta, where galectin-3 ablation was associated with an exacerbation of the disease [77][78][79][80][81], in the liver of the same animals, HFD-induced non-alcoholic steatohepatitis (NASH) was attenuated by galectin-3 ablation, as indicated by the lower extent of inflammation and fibrosis, the two hallmarks of NASH. Consistently, liver AGE and ALE levels and RAGE expression were decreased in galectin-3 deficient mice as opposed to wild-type.…”

Galectin-3 in acute coronary syndrome

“…Nevertheless, some Authors [26,27] suggested that Gal-3 can influence modified-LDL uptake by macrophages; particularly, Gal-3 has been demonstrated to play a major role in transforming macrophages into foam cells, which secrete Gal-3, attracting monocytes and macrophages. However, Gal-3 might influence plaque progression also avoiding the effective removal of modified lipoproteins, as shown by Iacobini in an experimental study in mice [28]. As suggested by an in vitro study, another observation supporting the pro-atherogenic role of Gal-3 is its binding with Lipopolysaccharide (LPS), which in turn exerts several pro-atherogenic effects [29].…”

Dangers Within

“…125 Increased AGE and RAGE levels, macrophage infiltration, fibrosis, and inflammation are found in the kidneys of mice that develop glomerular disease from an atherogenic high-fat diet; this lipid-induced renal injury is regulated in part by galectin-3. 126 TLR4 is up-regulated in mouse models of cryoglobulinemic membranoproliferative glomerulonephritis and localizes to podocytes of nephritic glomeruli; stimulation of podocytes with either TLR4 ligands or fibrinogen results in similar patterns of enhanced chemokine expression, suggesting that TLR4 functions as a DAMPs receptor for endogenous ligands and may mediate glomerular injury by stimulating innate immunity. 127 In nephrotoxic nephritis, a model of rapidly progressive glomerulonephritis, Hsp60 is released from kidneys and excreted in urine, and administration of Hsp60 exacerbates disease in a T cell-dependent manner.…”