title: Effects of aging and uninephrectomy on renal changes in Tsukuba hypertensive mice.
abstract: Renal dysfunction is accelerated by various factors such as hypertension, aging and diabetes. Glomerular hyper-filtration, considered one of the major risk factors leading to diabetic nephropathy, is often encountered in diabetic patients. However, the interrelationship of these risk factors during the course and development of renal dysfunction has not been fully elucidated. In this study, the effects of aging and uninephrectomy (UNx)-induced hyperfiltration on renal changes were investigated in Tsukuba hypertensive mice (THM) carrying both human renin and angiotensinogen genes. In THM, the urinary albumin/creatinine (Alb/Cr) ratio was elevated with age without a concomitant increase in the plasma Cr concentration. Moreover, the urinary neutrophil gelatinase-associated lipocalin/Cr (NGAL/Cr) ratio, the renal monocyte chemoattractant protein-1 (MCP-1) mRNA expression and the renal collagen type I α 2 (COL1A2) mRNA expression were also increased with age. Age-related albuminuria in THM is likely caused by renal tubular damage, enhanced inflammatory response and tubulointerstitial fibrosis. Furthermore, following UNx, the urinary Alb/Cr ratio and the plasma Cr concentration were increased in THM. The urinary NGAL/Cr ratio and the renal MCP-1 and COL1A2 mRNA expression were not affected by UNx. These results suggested that UNx-induced albuminuria in THM was caused by glomerular dysfunction, rather than renal tubular injury. In conclusion, this study demonstrated for the first time the effects of aging and UNx on renal changes in THM. These findings strongly reinforce the significance of applying a diversity of therapeutic approaches to the management of renal dysfunction.
authors.affiliation: Pharmacology Research Laboratories II, Mitsubishi Tanabe Pharma Corporation, Toda, Saitama 335-8505; ; Life Science Center, Tsukuba Advanced Research Alliance, Graduate School of Life and Environmental Sciences, University of Tsukuba, Tsukuba, Ibaraki 305-8577, Japan.
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Inui
authors.affiliation: Pharmacology Research Laboratories II, Mitsubishi Tanabe Pharma Corporation, Toda, Saitama 335-8505;
authors.forename: Hideki
authors.initials: H
authors.lastname: Mochida
authors.affiliation: Advanced Medical Research Laboratory, Mitsubishi Tanabe Pharma Corporation, Toda, Saitama 335-8505;
authors.forename: Fumiko
authors.initials: F
authors.lastname: Yamairi
authors.affiliation: Safety Research Laboratory, Mitsubishi Tanabe Pharma Corporation, Kisarazu, Chiba 292-0818;
authors.forename: Miyoko
authors.initials: M
authors.lastname: Okada
authors.affiliation: Life Science Center, Tsukuba Advanced Research Alliance, Graduate School of Life and Environmental Sciences, University of Tsukuba, Tsukuba, Ibaraki 305-8577, Japan.
authors.forename: Junji
authors.initials: J
authors.lastname: Ishida
authors.affiliation: Life Science Center, Tsukuba Advanced Research Alliance, Graduate School of Life and Environmental Sciences, University of Tsukuba, Tsukuba, Ibaraki 305-8577, Japan.
authors.forename: Akiyoshi
authors.initials: A
authors.lastname: Fukamizu
authors.affiliation: Pharmacology Research Laboratories II, Mitsubishi Tanabe Pharma Corporation, Toda, Saitama 335-8505;
authors.forename: Kenji
authors.initials: K
authors.lastname: Arakawa
keywords: Tsukuba hypertensive mice; aging; albuminuria; glomerular hyperfiltration; hypertension; renal disease