Development of age-dependent glomerular lesions in galectin-3/AGE-receptor-3 knockout mice

Abstract

. Development of agedependent glomerular lesions in galectin-3/AGE-receptor-3 knockout mice. Am J Physiol Renal Physiol 289: F611-F621, 2005. First published May 3, 2005 doi:10.1152/ajprenal.00435.2004.-Aging is characterized by renal functional and structural abnormalities resembling those observed in diabetes. These changes have been related to the progressive accumulation of advanced glycation end-products (AGEs) and cumulative oxidative stress occurring in both conditions. We previously reported that galectin-3 ablation is associated with increased susceptibility to diabetes-and AGE-induced glomerulopathy, thus indicating a protective role of galectin-3 as an AGE receptor. To investigate the role of the AGE/AGE receptor pathway in the pathogenesis of age-related renal disease, we evaluated the development of glomerular lesions in aging galectin-3 knockout (KO) vs. wild-type (WT) mice and their relation to the increased AGE levels and oxidative stress characterizing the aging process. KO mice showed significantly more pronounced age-dependent increases in proteinuria, albuminuria, glomerular sclerosis, and glomerular and mesangial areas, starting at 18 mo, as well as renal extracellular matrix mRNA and protein expression, starting at 12 mo vs. agematched WT mice. Circulating and renal AGEs, plasma isoprostane 8-epi-PGF 2␣ levels, glomerular content of the glycoxidation and lipoxidation products N ⑀ -carboxymethyllysine and 4-hydroxy-2-nonenal, and renal nuclear factor-B activity also increased more markedly with age in KO than WT mice. AGE levels correlated significantly with renal functional and structural parameters. These data indicate that aging galectin-3 KO mice develop more pronounced changes in renal function and structure than coeval WT mice, in parallel with a more marked degree of AGE accumulation, oxidative stress, and associated low-grade inflammation, thus supporting the concept that the AGE/AGE receptor pathway is implicated in agerelated renal disease.age-related glomerulopathy; advanced glycation end-products; advanced glycation end-product receptors; oxidative stress AGING IS A COMPLEX PATHOPHYSIOLOGICAL condition in which the function of many organ systems becomes altered, although it is unclear the extent to which these changes are the result of a normal aging process or of the interplay of age with chronic diseases that are more common in older people. Several changes in kidney function and structure have been detected in aged humans (31) and animals (4). The functional hallmark is a progressive decline of glomerular filtration rate, associated with reduced renal plasma flow and ultrafiltration coefficient, and increased filtration fraction and renal vascular resistance (19,31). From a morphological point of view, the glomerular number is reduced (36), and there is an increased prevalence of global glomerulosclerosis and tubulointerstitial fibrosis, preceded and accompanied by glomerular hypertrophy, mesangial matrix expansion, glomerular basement membrane thickening, and arteriolar hyal...

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.…”

Loss of galectin-3 impairs membrane polarisation of mouse enterocytes in vivo

“…The defects so far discovered in gal3 -/-mice are relatively mild (Bichara et al, 2006;Colnot et al, 1998;Colnot et al, 2001;Iacobini et al, 2005) and no intestinal deficits have ever been recorded (F.P., unpublished data). It will now be interesting to change the environment of these animals, for example by supplying different food diets.…”

Diabetic Nephropathy: Current and Novel Therapeutic Approaches to Prevent Its Development and Progression

“…The contribution of AGE-R3 to the development and progression of diabetic nephropathy has not been extensively researched. However, AGE-induced increases in the expression of AGE-R3 has been demonstrated in cultured endothelial cells and within renal tissues in the diabetic milieu (Iacobini, Oddi et al 2005;Kumar, Narang et al 2006). This however, may indicate a protective role for AGE-R3 given that AGE-R3 deficient mice develop more severe renal disease and have marked increases in renal AGE deposition (Iacobini, Oddi et al 2005).…”

“…However, AGE-induced increases in the expression of AGE-R3 has been demonstrated in cultured endothelial cells and within renal tissues in the diabetic milieu (Iacobini, Oddi et al 2005;Kumar, Narang et al 2006). This however, may indicate a protective role for AGE-R3 given that AGE-R3 deficient mice develop more severe renal disease and have marked increases in renal AGE deposition (Iacobini, Oddi et al 2005). Furthermore, AGE-R3 deficient mice develop albuminuria, mesangial expansion and fibrosis within the kidney cortex which is more pronounced with diabetes.…”