INDICATORS OF AGING KIDNEY, MEDIATORS OF EXTRACELLULAR MATRIX REMODELING

Abstract Background and Aims The main characteristics of aging kidney are age dependent glomerulosclerosis, tubular atrophy and interstitial fibrosis, therefore aging is now considered as an independent risk of chronic kidney disease. Extracellular matrix accumulation (ECM) is an early indicator of aging. Therefore in order to search for early indicator of aging kidney, we examined the expressions of regulators of ECM in the kidney in biologically aging and disease aging mice. Method C57BL/6 mice were studied at 2, 6, 12, 24 months of age, and leptin-deficient db/db mice were studied at 3, 6, 9 months of age. Gene and protein expressions of the kidney were examined as well as kidney injury markers in blood and urine. Results As expected, the biologically aging B6 mice exhibited progressive microalbuminuria during the lifespan. Systemically, the aging mice showed decreased levels of adiponectin, insulin and cholesterols. In the kidney tissue, proinflammatory and profibrotic gene expressions, in association with its regulators were significantly increased in age-dependent manners. At 24months, MCP-1, PAI-1, Collagen IV, MMP7, MMP9, angiotensin II, FGF23 and β-catenin gene expressions were significantly increased, whereas MMP2 and Snail, a direct activator of MMP-2 were significantly decreased. Protein expressions showed similar patterns. In high glucose condition, several markers showed diverse features in aging mice. As compared to db/m control, gene expressions of proinflammatory, profibrotic molecule as well as its regulators were all significantly increased in diabetic condition. Angiotensin II, FGF23, MCP-1, MMP7 and MMP9, TIMP-1 were significantly upregulated in diabetic kidney according to ages and interestingly Klotho was significantly downregulated in aged diabetic kidney. Snail and MMP2 showed no significant differences. Conclusion MMPs are involved in the crosstalk of the cells and surrounding extracellular matrix and can be considered as the marker of aging kidney. The regulators of ECM matrix seems to be different according to its’ pathological conditions. Human clinical data is needed to render the clinical significance.