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 Nε-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.

Advanced lipoxidation end-products mediate lipid-induced glomerular injury: role of receptor-mediated mechanisms / Iacobini, Carla; Menini, Stefano; Ricci, Carlo; A., Scipioni; V., Sansoni; A., Mazzitelli; Cordone, Samantha; C., Pesce; Pugliese, Francesco; F., Pricci; Pugliese, Giuseppe. - In: JOURNAL OF PATHOLOGY. - ISSN 0022-3417. - 218:3(2009), pp. 360-369. [10.1002/path.2536]

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

IACOBINI, carla;MENINI, Stefano;RICCI, Carlo;CORDONE, Samantha;PUGLIESE, Francesco;PUGLIESE, Giuseppe
2009

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 Nε-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.
advanced glycation endproduct receptors; advanced glycation endproducts; advanced lipoxidation endproducts; apoptosis; extracellular matrix; galectin-3; glomerulopathy; inflammation; lipids; oxidative stress; rage; scavenger receptors
01 Pubblicazione su rivista::01a Articolo in rivista
Advanced lipoxidation end-products mediate lipid-induced glomerular injury: role of receptor-mediated mechanisms / Iacobini, Carla; Menini, Stefano; Ricci, Carlo; A., Scipioni; V., Sansoni; A., Mazzitelli; Cordone, Samantha; C., Pesce; Pugliese, Francesco; F., Pricci; Pugliese, Giuseppe. - In: JOURNAL OF PATHOLOGY. - ISSN 0022-3417. - 218:3(2009), pp. 360-369. [10.1002/path.2536]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/359130
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