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Clinical and Experimental Nephrology
Published in: Clinical and Experimental Nephrology 5/2016

01-10-2016 | Original Article

Klotho attenuates renal hypertrophy and glomerular injury in Ins2Akita diabetic mice

Authors: Hiroyuki Kadoya, Minoru Satoh, Yoshisuke Haruna, Tamaki Sasaki, Naoki Kashihara

Published in: Clinical and Experimental Nephrology | Issue 5/2016

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Abstract

Background

Expression of klotho, the renoprotective anti-aging gene, is decreased in diabetic model kidneys. We hypothesized that klotho protein attenuates renal hypertrophy and glomerular injury in a mouse model of diabetic nephropathy.

Methods

Klotho transgenic (KLTG) mice were crossed with spontaneously diabetic Ins2Akita (AKITA) mice. Glomerular morphology, macrophage infiltration, urinary albumin excretion and urinary 8-hydroxy-2-deoxy guanosine excretion were examined. In vitro, human glomerular endothelial cells were stimulated with high glucose with or without recombinant klotho, and calpain activity and proinflammatory cytokine expressions were measured.

Results

We found that klotho protein overexpression attenuates renal hypertrophy and glomerular injury in this mouse model of diabetic nephropathy. Klotho overexpression attenuated renal hypertrophy, albuminuria, glomerular mesangial expansion, and endothelial glycocalyx loss in the AKITA mice. AKITA mice exhibit high levels of urinary 8-hydroxy-2-deoxy guanosine excretion. In the presence of klotho overexpression, this effect was reversed. In addition, the glomerular macrophage infiltration characteristic of AKITA mice was attenuated in KLTG-AKITA mice. In human glomerular endothelial cells, high glucose induced calpain activity. This effect was suppressed by expression of recombinant klotho, which also suppressed the induction of proinflammatory cytokines.

Conclusion

Our data suggest klotho protein protects against diabetic nephropathy through multiple pathways.
Literature
1.
Kuro-o M, Matsumura Y, Aizawa H, Kawaguchi H, Suga T, Utsugi T, Ohyama Y, Kurabayashi M, Kaname T, Kume E, Iwasaki H, Iida A, Shiraki-Iida T, Nishikawa S, Nagai R, Nabeshima YI. Mutation of the mouse klotho gene leads to a syndrome resembling ageing. Nature. 1997;390:45–51.CrossRefPubMed
2.
Haruna Y, Kashihara N, Satoh M, Tomita N, Namikoshi T, Sasaki T, Fujimori T, Xie P, Kanwar YS. Amelioration of progressive renal injury by genetic manipulation of Klotho gene. Proc Natl Acad Sci USA. 2007;104:2331–6.CrossRefPubMedPubMedCentral
3.
Satoh M, Nagasu H, Morita Y, Yamaguchi TP, Kanwar YS, Kashihara N. Klotho protects against mouse renal fibrosis by inhibiting Wnt signaling. Am J Physiol Renal Physiol. 2012;303:F1641–51.CrossRefPubMedPubMedCentral
4.
Nagasu H, Satoh M, Kuwabara A, Yorimitsu D, Kidokoro K, Nishi Y, Tomita N, Sasaki T, Kashihara N. Overexpression of klotho protein modulates uninephrectomy-induced compensatory renal hypertrophy by suppressing IGF-I signals. Biochem Biophys Res Commun. 2011;407:39–43.CrossRefPubMed
5.
Ruggenenti P, Remuzzi G. Nephropathy of type-2 diabetes mellitus. J Am Soc Nephrol. 1998;9:2157–69.PubMed
6.
Asai O, Nakatani K, Tanaka T, Sakan H, Imura A, Yoshimoto S, Samejima K, Yamaguchi Y, Matsui M, Akai Y, Konishi N, Iwano M, Nabeshima Y, Saito Y. Decreased renal alpha-Klotho expression in early diabetic nephropathy in humans and mice and its possible role in urinary calcium excretion. Kidney Int. 2012;81:539–47.CrossRefPubMed
7.
Lin Y, Kuro-o M, Sun Z. Genetic deficiency of anti-aging gene klotho exacerbates early nephropathy in STZ-induced diabetes in male mice. Endocrinology. 2013;154:3855–63.CrossRefPubMedPubMedCentral
8.
Zhao Y, Banerjee S, Dey N, LeJeune WS, Sarkar PS, Brobey R, Rosenblatt KP, Tilton RG, Choudhary S. Klotho depletion contributes to increased inflammation in kidney of the db/db mouse model of diabetes via RelA (serine)536 phosphorylation. Diabetes. 2011;60:1907–16.CrossRefPubMedPubMedCentral
9.
Yoshioka M, Kayo T, Ikeda T, Koizumi A. A novel locus, Mody4, distal to D7Mit189 on chromosome 7 determines early-onset NIDDM in nonobese C57BL/6 (Akita) mutant mice. Diabetes. 1997;46:887–94.CrossRefPubMed
10.
Kurosu H, Yamamoto M, Clark JD, Pastor JV, Nandi A, Gurnani P, McGuinness OP, Chikuda H, Yamaguchi M, Kawaguchi H, Shimomura I, Takayama Y, Herz J, Kahn CR, Rosenblatt KP, Kuro-o M. Suppression of aging in mice by the hormone Klotho. Science. 2005;309:1829–33.CrossRefPubMedPubMedCentral
11.
Nagasu H, Satoh M, Fujimoto S, Tomita N, Sasaki T, Kashihara N. Azelnidipine attenuates glomerular damage in Dahl salt-sensitive rats by suppressing sympathetic nerve activity. Hypertens Res. 2012;35:348–55.CrossRefPubMed
12.
13.
Aizawa H, Saito Y, Nakamura T, Inoue M, Imanari T, Ohyama Y, Matsumura Y, Masuda H, Oba S, Mise N, Kimura K, Hasegawa A, Kurabayashi M, Kuro-o M, Nabeshima Y, Nagai R. Downregulation of the Klotho gene in the kidney under sustained circulatory stress in rats. Biochem Biophys Res Commun. 1998;249:865–71.CrossRefPubMed
14.
Sastre C, Rubio-Navarro A, Buendia I, Gomez-Guerrero C, Blanco J, Mas S, Egido J, Blanco-Colio LM, Ortiz A, Moreno JA. Hyperlipidemia-associated renal damage decreases Klotho expression in kidneys from ApoE knockout mice. PLoS ONE. 2013;8:e83713.CrossRefPubMedPubMedCentral
15.
Mogensen CE, Andersen MJ. Increased kidney size and glomerular filtration rate in untreated juvenile diabetes: normalization by insulin-treatment. Diabetologia. 1975;11:221–4.CrossRefPubMed
16.
Thomas MC, Burns WC, Cooper ME. Tubular changes in early diabetic nephropathy. Adv Chronic Kidney Dis. 2005;12:177–86.CrossRefPubMed
17.
Flyvbjerg A, Landau D, Domene H, Hernandez L, Gronbaek H, LeRoith D. The role of growth hormone, insulin-like growth factors (IGFs), and IGF-binding proteins in experimental diabetic kidney disease. Metabolism. 1995;44:67–71.CrossRefPubMed
18.
Flyvbjerg A, Frystyk J, Osterby R, Orskov H. Kidney IGF-I and renal hypertrophy in GH-deficient diabetic dwarf rats. Am J Physiol. 1992;262:E956–62.PubMed
19.
Kidokoro K, Satoh M, Channon KM, Yada T, Sasaki T, Kashihara N. Maintenance of endothelial guanosine triphosphate cyclohydrolase I ameliorates diabetic nephropathy. J Am Soc Nephrol. 2013;24:1139–50.CrossRefPubMedPubMedCentral
20.
Haraldsson B, Nystrom J, Deen WM. Properties of the glomerular barrier and mechanisms of proteinuria. Physiol Rev. 2008;88:451–87.CrossRefPubMed
21.
van den Berg BM, Vink H, Spaan JA. The endothelial glycocalyx protects against myocardial edema. Circ Res. 2003;92:592–4.CrossRefPubMed
22.
Salmon AH, Ferguson JK, Burford JL, Gevorgyan H, Nakano D, Harper SJ, Bates DO, Peti-Peterdi J. Loss of the endothelial glycocalyx links albuminuria and vascular dysfunction. J Am Soc Nephrol. 2012;23:1339–50.CrossRefPubMedPubMedCentral
23.
Kuwabara A, Satoh M, Tomita N, Sasaki T, Kashihara N. Deterioration of glomerular endothelial surface layer induced by oxidative stress is implicated in altered permeability of macromolecules in Zucker fatty rats. Diabetologia. 2010;53:2056–65.CrossRefPubMedPubMedCentral
24.
25.
Sorimachi H, Hata S, Ono Y. Calpain chronicle–an enzyme family under multidisciplinary characterization. Proc Jpn Acad Ser B Phys Biol Sci. 2011;87:287–327.CrossRefPubMedPubMedCentral
26.
Wang S, Peng Q, Zhang J, Liu L. Na+/H+ exchanger is required for hyperglycaemia-induced endothelial dysfunction via calcium-dependent calpain. Cardiovasc Res. 2008;80:255–62.CrossRefPubMed
27.
Terada M, Yasuda H, Kikkawa R. Delayed Wallerian degeneration and increased neurofilament phosphorylation in sciatic nerves of rats with streptozocin-induced diabetes. J Neurol Sci. 1998;155:23–30.CrossRefPubMed
28.
Nangle MR, Cotter MA, Cameron NE. The calpain inhibitor, A-705253, corrects penile nitrergic nerve dysfunction in diabetic mice. Eur J Pharmacol. 2006;538:148–53.CrossRefPubMed
29.
Stalker TJ, Skvarka CB, Scalia R. A novel role for calpains in the endothelial dysfunction of hyperglycemia. FASEB J. 2003;17:1511–3.PubMed
30.
Manya H, Inomata M, Fujimori T, Dohmae N, Sato Y, Takio K, Nabeshima Y, Endo T. Klotho protein deficiency leads to overactivation of mu-calpain. J Biol Chem. 2002;277:35503–8.CrossRefPubMed
Metadata
Title
Klotho attenuates renal hypertrophy and glomerular injury in Ins2Akita diabetic mice
Authors
Hiroyuki Kadoya
Minoru Satoh
Yoshisuke Haruna
Tamaki Sasaki
Naoki Kashihara
Publication date
01-10-2016
Publisher
Springer Japan
Published in
Clinical and Experimental Nephrology / Issue 5/2016
Print ISSN: 1342-1751
Electronic ISSN: 1437-7799
DOI
https://doi.org/10.1007/s10157-015-1202-3

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