Effects of aging and uninephrectomy on renal changes in Tsukuba hypertensive mice

Inui,Yosuke; Mochida,Hideki; Yamairi,Fumiko; Okada,Miyoko; Ishida,Junji; Fukamizu,Akiyoshi; Arakawa,Kenji

doi:10.3892/br.2013.74

Effects of aging and uninephrectomy on renal changes in Tsukuba hypertensive mice

Authors:
- Yosuke Inui
- Hideki Mochida
- Fumiko Yamairi
- Miyoko Okada
- Junji Ishida
- Akiyoshi Fukamizu
- Kenji Arakawa
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Affiliations: Pharmacology Research Laboratories II, Mitsubishi Tanabe Pharma Corporation, Toda, Saitama 335‑8505, Japan, Advanced Medical Research Laboratory, Mitsubishi Tanabe Pharma Corporation, Toda, Saitama 335‑8505, Japan, Safety Research Laboratory, Mitsubishi Tanabe Pharma Corporation, Kisarazu, Chiba 292-0818, Japan, Life Science Center, Tsukuba Advanced Research Alliance, Graduate School of Life and Environmental Sciences, University of Tsukuba, Tsukuba, Ibaraki 305-8577, Japan
Published online on: March 7, 2013 https://doi.org/10.3892/br.2013.74
Pages: 359-364

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Abstract

Renal dysfunction is accelerated by various factors such as hypertension, aging and diabetes. Glomerular hyperfiltration, 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 Alb̸Cr 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.

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1	Levey AS, Eckardt KU, Tsukamoto Y, et al: Definition and classification of chronic kidney disease: a position statement from Kidney Disease: Improving Global Outcomes (KDIGO). Kidney Int. 67:2089–2100. 2005. View Article : Google Scholar : PubMed/NCBI
2	Jungers P: Screening for renal insufficiency: is it worth while? is it feasible? Nephrol Dial Transplant. 14:2082–2084. 1999. View Article : Google Scholar : PubMed/NCBI
3	Akiba T, Nakai S, Shinzato T, et al: Why has the gross mortality of dialysis patients increased in Japan? Kidney Int. 57:S60–S65. 2000. View Article : Google Scholar
4	Weiner DE, Tighiouart H, Amin MG, et al: Chronic kidney disease as a risk factor for cardiovascular disease and all-cause mortality: a pooled analysis of community-based studies. J Am Soc Nephrol. 15:1307–1315. 2004. View Article : Google Scholar : PubMed/NCBI
5	Jafar TH, Stark PC, Schmid CH, et al: Progression of chronic kidney disease: the role of blood pressure control, proteinuria, and angiotensin-converting enzyme inhibition: a patient-level meta-analysis. Ann Intern Med. 139:244–252. 2003. View Article : Google Scholar : PubMed/NCBI
6	Iseki K, Ikemiya Y, Iseki C and Takishita S: Proteinuria and the risk of developing end-stage renal disease. Kidney Int. 63:1468–1474. 2003. View Article : Google Scholar : PubMed/NCBI
7	Imai E, Horio M, Iseki K, et al: Prevalence of chronic kidney disease (CKD) in the Japanese general population predicted by the MDRD equation modified by a Japanese coefficient. Clin Exp Nephrol. 11:156–163. 2007. View Article : Google Scholar : PubMed/NCBI
8	Coresh J, Astor BC, Greene T, Eknoyan G and Levey AS: Prevalence of chronic kidney disease and decreased kidney function in the adult US population: Third National Health and Nutrition Examination Survey. Am J Kidn Dis. 41:1–12. 2003. View Article : Google Scholar : PubMed/NCBI
9	Tozawa M, Iseki K, Iseki C, Kinjo K, Ikemiya Y and Takishita S: Blood pressure predicts risk of developing end-stage renal disease in men and women. Hypertension. 41:1341–1345. 2003. View Article : Google Scholar : PubMed/NCBI
10	Feld LG, Van Liew JB, Galaske RG and Boylan JW: Selectivity of renal injury and proteinuria in the spontaneously hypertensive rat. Kidney Int. 12:332–343. 1977. View Article : Google Scholar : PubMed/NCBI
11	Levine DZ: Can rodent models of diabetic kidney disease clarify the significance of early hyperfiltration?: recognizing clinical and experimental uncertainties. Clin Sci (Lond). 114:109–118. 2008. View Article : Google Scholar
12	Yamagata K, Ishida K, Sairenchi T, et al: Risk factors for chronic kidney disease in a community-based population: a 10-year follow-up study. Kidney Int. 71:159–166. 2007.PubMed/NCBI
13	Fukamizu A, Sugimura K, Takimoto E, et al: Chimeric renin-angiotensin system demonstrates sustained increase in blood pressure of transgenic mice carrying both human renin and human angiotensinogen genes. J Biol Chem. 268:11617–11621. 1993.
14	Fukamizu A, Seo MS, Hatae T, et al: Tissue-specific expression of the human renin gene in transgenic mice. Biochem Biophys Res Commun. 165:826–832. 1989. View Article : Google Scholar : PubMed/NCBI
15	Takahashi S, Fukamizu A, Hasegawa T, et al: Expression of the human angiotensinogen gene in transgenic mice and transfected cells. Biochem Biophys Res Commun. 180:1103–1109. 1991. View Article : Google Scholar : PubMed/NCBI
16	Kai T, Sugimura K, Shimada S, Kurooka A, Takenaka T and Ishikawa K: Inhibitory effects of a subdepressor dose of L-158,809, an angiotensin II type 1 receptor antagonist, on cardiac hypertrophy and nephropathy via the activated human renin-angiotensin system in double transgenic mice with hyper-tension. Jpn Circ J. 62:599–603. 1998. View Article : Google Scholar
17	Kai T, Kino H and Ishikawa K: Role of the renin-angiotensin system in cardiac hypertrophy and renal glomerular sclerosis in transgenic hypertensive mice carrying both human renin and angiotensinogen genes. Hypertens Res. 21:39–46. 1998. View Article : Google Scholar
18	Shimokama T, Haraoka S, Horiguchi H, Sugiyama F, Murakami K and Watanabe T: The Tsukuba hypertensive mouse (transgenic mouse carrying human genes for both renin and angiotensinogen) as a model of human malignant hypertension: development of lesions and morphometric analysis. Virchows Archiv. 432:169–175. 1998. View Article : Google Scholar
19	Hsu CY, Iribarren C, McCulloch CE, Darbinian J and Go AS: Risk factors for end-stage renal disease: 25-year follow-up. Arch Inter Med. 169:342–350. 2009.PubMed/NCBI
20	Helal I, Fick-Brosnahan GM, Reed-Gitomer B and Schrier RW: Glomerular hyperfiltration: definitions, mechanisms and clinical implications. Nat Rev Nephrol. 8:293–300. 2012. View Article : Google Scholar : PubMed/NCBI
21	Russo LM, Sandoval RM, Campos SB, Molitoris BA, Comper WD and Brown D: Impaired tubular uptake explains albuminuria in early diabetic nephropathy. J Am Soc Nephrol. 20:489–494. 2009. View Article : Google Scholar : PubMed/NCBI
22	Comper WD, Haraldsson B and Deen WM: Resolved: normal glomeruli filter nephrotic levels of albumin. J Am Soc Nephrol. 19:427–432. 2008. View Article : Google Scholar : PubMed/NCBI
23	Birn H and Christensen EI: Renal albumin absorption in physiology and pathology. Kidney Int. 69:440–449. 2006. View Article : Google Scholar : PubMed/NCBI
24	Wada T, Furuichi K, Sakai N, et al: Up-regulation of monocyte chemoattractant protein-1 in tubulointerstitial lesions of human diabetic nephropathy. Kidney Int. 58:1492–1499. 2000. View Article : Google Scholar : PubMed/NCBI
25	Korrapati MC, Shaner BE, Neely BA, Alge JL, Arthur JM and Schnellmann RG: Diabetes-induced renal injury in rats is attenuated by suramin. J Pharmacol Exp Ther. 343:34–43. 2012. View Article : Google Scholar : PubMed/NCBI
26	Eardley KS, Zehnder D, Quinkler M, et al: The relationship between albuminuria, MCP-1//CCL2, and interstitial macrophages in chronic kidney disease. Kidney Int. 69:1189–1197. 2006. View Article : Google Scholar : PubMed/NCBI
27	Taniguchi H, Kojima R, Sade H, Furuya M, Inomata N and Ito M: Involvement of MCP-1 in tubulointerstitial fibrosis through massive proteinuria in anti-GBM nephritis induced in WKY rats. J Clin Immunol. 27:409–429. 2007. View Article : Google Scholar : PubMed/NCBI
28	Hostetter TH, Olson JL, Rennke HG, Venkatachalam MA and Brenner BM: Hyperfiltration in remnant nephrons: a potentially adverse response to renal ablation. Am J Physiol. 241:F85–F93. 1981.PubMed/NCBI
29	Kanwar YS, Danesh FR and Chugh SS: Contribution of proteoglycans towards the integrated functions of renal glomerular capillaries: a historical perspective. Am J Pathol. 171:9–13. 2007. View Article : Google Scholar : PubMed/NCBI
30	Haraldsson B, Nyström J and Deen WM: Properties of the glomerular barrier and mechanisms of proteinuria. Physiol Rev. 88:451–487. 2008. View Article : Google Scholar : PubMed/NCBI
31	Broekhuizen LN, Lemkes BA, Mooij HL, et al: Effect of sulodexide on endothelial glycocalyx and vascular permeability in patients with type 2 diabetes mellitus. Diabetologia. 53:2646–2655. 2010. View Article : Google Scholar : PubMed/NCBI
32	Salmon AHJ, Ferguson JK, Burford JL, et al: Loss of the endothelial glycocalyx links albuminuria and vascular dysfunction. J Am Soc Nephrol. 23:1339–1350. 2012. View Article : Google Scholar : PubMed/NCBI