1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
F810
GBD 2019 Diseases and Injuries Collaborators. Global burden of
369 diseases and injuries in 204 countries and territories, 1990–
2019: a systematic analysis for the Global Burden of Disease Study
2019. Lancet 396: 1204–1222, 2020. doi:10.1016/S0140-6736(20)
30925-9.
Rodier F, Campisi J. Four faces of cellular senescence. J Cell Biol
192: 547–556, 2011. doi:10.1083/jcb.201009094.
Zhou XJ, Rakheja D, Yu X, Saxena R, Vaziri ND, Silva FG. The aging
kidney. Kidney Int 74: 710–720, 2008. doi:10.1038/ki.2008.319.
Collado M, Blasco MA, Serrano M. Cellular senescence in cancer
and aging. Cell 130: 223–233, 2007. doi:10.1016/j.cell.2007.07.003.
Kuro-O M. Klotho as a regulator of oxidative stress and senescence.
Biol Chem 389: 233–241, 2008. doi:10.1515/BC.2008.028.
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 Y. Mutation of
the mouse klotho gene leads to a syndrome resembling ageing.
Nature 390: 45–51, 1997. doi:10.1038/36285.
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, Kuroo M. Suppression of aging in mice by the hormone Klotho. Science
309: 1829–1833, 2005. doi:10.1126/science.1112766.
Yamazaki Y, Imura A, Urakawa I, Shimada T, Murakami J, Aono Y,
Hasegawa H, Yamashita T, Nakatani K, Saito Y, Okamoto N,
Kurumatani N, Namba N, Kitaoka T, Ozono K, Sakai T, Hataya H,
Ichikawa S, Imel EA, Econs MJ, Nabeshima Y. Establishment of
sandwich ELISA for soluble alpha-Klotho measurement: age-dependent change of soluble alpha-Klotho levels in healthy subjects.
Biochem Biophys Res Commun 398: 513–518, 2010. doi:10.1016/j.
bbrc.2010.06.110.
Sakan H, Nakatani K, Asai O, Imura A, Tanaka T, Yoshimoto S,
Iwamoto N, Kurumatani N, Iwano M, Nabeshima Y, Konishi N,
Saito Y. Reduced renal a-Klotho expression in CKD patients and its
effect on renal phosphate handling and vitamin D metabolism. PLoS
One 9: e8630, 2014. doi:10.1371/journal.pone.0086301.
Sugiura H, Yoshida T, Shiohira S, Kohei J, Mitobe M, Kurosu H,
Kuro-O M, Nitta K, Tsuchiya K. Reduced Klotho expression level in
kidney aggravates renal interstitial fibrosis. Am J Physiol Renal
Physiol 302: F1252–F1264, 2012. doi:10.1152/ajprenal.00294.2011.
Haruna Y, Kashihara N, Satoh M, Tomita M, 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 104: 2331–2336, 2007. doi:10.1073/pnas.0611079104.
Hu MC, Shi M, Gillings N, Flores B, Takahashi M, Kuro-O M, Moe
OW. Recombinant a-Klotho may be prophylactic and therapeutic for
acute to chronic kidney disease progression and uremic cardiomyopathy. Kidney Int 91: 1104–1114, 2017. doi:10.1016/j.kint.2016.10.034.
Kadoya H, Satoh M, Haruna Y, Sasaki T, Kashihara N. Klotho
attenuates renal hypertrophy and glomerular injury in Ins2Akita diabetic mice. Clin Exp Nephrol 20: 671–678, 2016. doi:10.1007/s10157015-1202-3.
Kurosu H, Ogawa Y, Miyoshi M, Yamamoto M, Nandi A,
Rosenblatt KP, Baum MG, Schiavi S, Hu M, Moe OW, Kuro-O M.
Regulation of fibroblast growth factor-23 signaling by klotho. J Biol
Chem 281: 6120–6123, 2006. doi:10.1074/jbc.C500457200.
Doi S, Zou Y, Togao O, Pastor JV, John GB, Wang L, Shiizaki K,
Gotschall R, Schiavi S, Yorioka N, Takahashi M, Boothman DA,
Kuro-O M. Klotho inhibits transforming growth factor-b1 (TGF-b1) signaling and suppresses renal fibrosis and cancer metastasis in mice.
J Biol Chem 286: 8655–8665, 2011. doi:10.1074/jbc.M110.174037.
Liu H, Fergusson MM, Castilho RM, Liu J, Cao L, Chen J, Malide D,
Rovira II, Schimel D, Kuo CJ, Gutkind JS, Hwang PM, Finkel T.
Augmented Wnt signaling in a mammalian model of accelerated
aging. Science 317: 803–806, 2007. doi:10.1126/science.1143578.
Hu MC, Shi M, Zhang J, Pastor J, Nakatani T, Lanske B, Razzaque
MS, Rosenblatt KP, Baum MG, Kuro-O M, Moe OW. Klotho: a novel
phosphaturic substance acting as an autocrine enzyme in the renal
proximal tubule. FASEB J 24: 3438–3450, 2010. doi:10.1096/fj.10154765.
Alexander RT, Woudenberg-Vrenken TE, Buurman J, Dijkman H,
van der Eerden BC, van Leeuwen JP, Bindels RJ, Hoenderop JG.
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
32.
33.
34.
35.
36.
37.
38.
39.
Klotho prevents renal calcium loss. J Am Soc Nephrol 20: 2371–
2379, 2009. doi:10.1681/ASN.2008121273.
Cha S-K, Hu M-C, Kurosu H, Kuro-o M, Moe O, Huang C-L.
Regulation of renal outer medullary potassium channel and renal
K þ excretion by Klotho. Mol Pharmacol 76: 38–46, 2009. doi:10.1124/
mol.109.055780.
Liu F, Wu S, Ren H, Gu J. Klotho suppresses RIG-I-mediated senescence-associated inflammation. Nat Cell Biol 13: 254–262, 2011.
doi:10.1038/ncb2167.
Meng XM, Nikolic-Paterson DJ, Hu. L. TGF-b: the master regulator
of fibrosis. Nat Rev Nephrol 12: 325–338, 2016. doi:10.1038/
nrneph.2016.
Tominaga K, Suzuki IH. TGF-b signaling in cellular senescence and
aging-related pathology. Int J Mol Sci 20: 5002, 2019. doi:10.3390/
ijms20205002.
Liu RM, Desai LP. Reciprocal regulation of TGF-b and reactive oxygen species: a perverse cycle for fibrosis. Redox Biol 6: 565–577,
2015. doi:10.1016/j.redox.2015.09.009.
Panesso MC, Shi M, Cho HJ, Paek J, Ye J, Moe OW, Hu MC. Klotho
has dual protective effects on cisplatin-induced acute kidney injury.
Kidney Int 85: 855–870, 2014. doi:10.1038/ki.2013.489.
Hall BM, Balan V, Gleiberman AS, Strom E, Krasnov P, Virtuoso
LP, Rydkina E, Vujcic S, Balan K, Gitlin I, Leonova K, Polinsky A,
Chernova OB, Gudkov AV. Aging of mice is associated with p16
(Ink4a)- and b-galactosidase-positive macrophage accumulation that
can be induced in young mice by senescent cells. Aging (Albany
NY) 8: 1294–1315, 2016. doi:10.18632/aging.100991.
Rule AD, Amer H, Cornell LD, Taler SJ, Cosio FG, Kremers WK,
Textor SC, Stegall MD. The association between age and nephrosclerosis on renal biopsy among healthy adults. Ann Intern Med 152:
561–567, 2010. doi:10.7326/0003-4819-152-9-201005040-00006.
Yang HC, Fogo AB. Fibrosis and renal aging. Kidney Int Suppl (2011)
4: 75–78, 2014. doi:10.1038/kisup.2014.14.
LeBleu VS, Taduri G, O'Connell J, Teng Y, Cooke VG, Woda C,
Sugimoto H, Kalluri R. Origin and function of myofibroblasts in kidney fibrosis. Nat Med 19: 1047–1053, 2013. doi:10.1038/nm.3218.
Kuro-O M. Klotho and aging. Biochim Biophys Acta 1790: 1049–
1058, 2009. doi:10.1016/j.bbagen.2009.02.005.
Ahsan H. 3-Nitrotyrosine: a biomarker of nitrogen free radical species modified proteins in systemic autoimmunogenic conditions.
Hum Immunol 74: 1392–1399, 2013. doi:10.1016/j.humimm.2013.06.
009.
Candas D, Li JJ. MnSOD in oxidative stress response-potential regulation via mitochondrial protein influx. Antioxid Redox Signal 20:
1599–1617, 2014. doi:10.1089/ars.2013.5305.
Zhang YE. Non-Smad pathways in TGF-beta signaling. Cell Res 19:
128–139, 2009. doi:10.1038/cr.2008.328.
Sergi C, Shen F, Liu SM. Insulin/IGF-1R, SIRT1, and FOXOs pathways—an intriguing interaction platform for bone and osteosarcoma. Front Endocrinol (Lausanne) 10: 93, 2019. doi:10.3389/
fendo.2019.00093.
Mitobe M, Yoshida T, Sugiura H, Shirota S, Tsuchiya K, Nihei H.
Oxidative stress decreases klotho expression in a mouse kidney
cell line. Nephron Exp Nephrol 101: e67–e74, 2005. doi:10.1159/
000086500.
Yoon HE, Ghee JY, Piao SG, Song JH, Han DH, Kim S, Ohashi N,
Kobori H, Kuro-O M, Yang CW. Angiotensin II blockade upregulates
the expression of klotho, the anti-ageing gene, in an experimental
model of chronic cyclosporine nephropathy. Nephrol Dial Transplant
26: 800–813, 2011. doi:10.1093/ndt/gfq537.
Irifuku T, Doi S, Sasaki K, Doi T, Nakashima A, Ueno T, Yamada K,
Arihiro K, Kohno N, Masaki T. Inhibition of H3K9 histone methyltransferase G9a attenuates renal fibrosis and retains klotho expression. Kidney Int 89: 147–157, 2016. doi:10.1038/ki.2015.291.
Morii K, Yamasaki S, Doi S, Irifuku T, Sasaki K, Doi T, Nakashima
A, Arihiro K, Masaki T. Micro RNA-200c regulates KLOTHO expression in human kidney cells under oxidative stress. PLoS One 14:
e0218468, 2019. doi:10.1371/journal.pone.0218468.
Vlassara H, Torreggiani M, Post JB, Zheng F, Uribarri J, Striker GE.
Role of oxidants/inflammation in declining renal function in chronic
kidney disease and normal aging. Kidney Int 76, Suppl 114: S3–S11,
2009. doi:10.1038/ki.2009.401.
Kim JH, Xie J, Hwang KH, Wu YL, Oliver N, Eom M, Park KS,
Barrezueta N, Kong ID, Fracasso RP, Huang C-L, Cha SK. Klotho
AJP-Renal Physiol doi:10.1152/ajprenal.00609.2020 www.ajprenal.org
Downloaded from journals.physiology.org/journal/ajprenal at Hiroshima Daigaku (133.041.093.090) on November 29, 2021.
KLOTHO AND RENAL AGING
40.
41.
42.
43.
44.
45.
46.
47.
48.
49.
50.
51.
52.
53.
may ameliorate proteinuria by targeting TRPC6 channels in podocytes. J Am Soc Nephrol 28: 140–151, 2017. doi:10.1681/
ASN.2015080888.
Kanbay M, Demiray A, Afsar B, Covic A, Tapoi L, Ureche C, Ortiz A.
Role of Klotho in the development of essential hypertension.
Hypertension 77: 740–750, 2021. doi:10.1161/HYPERTENSIONAHA.
120.16635.
Kawarazaki W, Mizuno R, Nishimoto M, Ayuzawa N, Hirohama D,
Ueda K, Kawakami-Mori F, Oba S, Marumo T, Fujita T. Salt causes
aging-associated hypertension via vascular Wnt5a under Klotho
deficiency. J Clin Invest 130: 4152–4166, 2020. doi:10.1172/
JCI134431.
Mizuno M, Mitchell JH, Crawford S, Huang C-L, Maalouf N, Hu MC, Moe OW, Smith SA, Vongpatanasin W. High dietary phosphate
intake induces hypertension and augments exercise pressor reflex
function in rats. Am J Physiol Regul Integr Comp Physiol 311: R39–
R48, 2016. doi:10.1152/ajpregu.00124.2016.
Villa-Etchegoyen C, Lombarte M, Matamoros N, Belizán JM,
Cormick G. Mechanisms involved in the relationship between low
calcium intake and high blood pressure. Nutrients 11: 1112, 2019.
doi:10.3390/nu11051112.
Wright JR, Duggal A, Thomas R, Reeve R, Roberts ISD, Kalra PA.
Clinicopathological correlation in biopsy-proven atherosclerotic nephropathy: implications for renal functional outcome in atherosclerotic renovascular disease. Nephrol Dial Transplant 16: 765–770,
2001. doi:10.1093/ndt/16.4.765.
Liu Y. Renal fibrosis: new insights into the pathogenesis and therapeutics. Kidney Int 69: 213–217, 2006. doi:10.1038/sj.ki.5000054.
Meng XM, Tang PMK, Li J, Lan HY. TGF-b/Smad signaling in renal fibrosis. Front Physiol 6: 82, 2015. doi:10.3389/fphys.2015.00082.
Schnaper HW, Hayashida T, Poncelet AC. It's a Smad world: regulation of TGF-beta signaling in the kidney. J Am Soc Nephrol 13: 1126–
1128, 2002. doi:10.1681/ASN.V1341126.
J. Mechanisms of TGF-beta signaling from cell
Shi Y, Massague
membrane to the nucleus. Cell 113: 685–700, 2003. doi:10.1016/
s0092-8674(03)00432-x.
Soji K, Doi S, Nakashima A, Sasaki K, Doi T, Masaki T.
Deubiquitinase inhibitor PR-619 reduces Smad4 expression and suppresses renal fibrosis in mice with unilateral ureteral obstruction.
PLoS One 13: e0202409, 2018. doi:10.1371/journal.pone.0202409.
Zhou J, Liu S, Guo L, Wang R, Chen J, Shen J. NMDA receptormediated CaMKII/ERK activation contributes to renal fibrosis. BMC
Nephrol 21: 392, 2020. doi:10.1186/s12882-020-02050-x.
Ma FY, Flanc RS, Tesch GH, Han Y, Atkins RC, Bennett BL,
Friedman GC, Fan JH, Nikolic-Paterson DJ. A pathogenic role for cJun amino-terminal kinase signaling in renal fibrosis and tubular cell
apoptosis. J Am Soc Nephrol 18: 472–484, 2007. doi:10.1681/ASN.
2006060604.
Lee J, An JN, Hwang JH, Lee H, Lee JP, Kim SG. p38 MAPK activity
is associated with the histological degree of interstitial fibrosis in IgA
nephropathy patients. PLoS One 14: e0213981, 2019. doi:10.1371/
journal.pone.0213981.
Kattla JJ, Carew RM, Heljic M, Godson C, Brazil DK. Protein kinase
B/Akt activity is involved in renal TGF-b1-driven epithelial-mesenchymal transition in vitro and in vivo. Am J Physiol Renal Physiol 295:
F215–F225, 2008. doi:10.1152/ajprenal.00548.2007.
54.
55.
56.
57.
58.
59.
60.
61.
62.
63.
64.
65.
66.
67.
68.
Katz M, Amit I, Yarden Y. Regulation of MAPKs by growth factors
and receptor tyrosine kinases. Biochim Biophys Acta 1773: 1161–1176,
2007. doi:10.1016/j.bbamcr.2007.01.002.
Manning BD, Cantley LC. AKT/PKB signaling: navigating downstream. Cell 129: 1261–1274, 2007. doi:10.1016/j.cell.2007.06.009.
Shimoda H, Doi S, Nakashima A, Sasaki K, Doi T, Masaki T.
Inhibition of the H3K4 methyltransferase MLL1/WDR5 complex
attenuates renal senescence in ischemia reperfusion mice by
reduction of p16INK4a. Kidney Int 96: 1162–1175, 2019. doi:10.1016/j.
kint.2019.06.021.
Wrzesinski SH, Wan YY, Flavell RA. Transforming growth factor-b
and the immune response: implications for anticancer therapy. Clin
Cancer Res 13: 5262–5270, 2007. doi:10.1158/1078-0432.CCR-071157.
Jang HS, Han SJ, Kim JI, Lee S, Lipschutz JH, Park KM.
Activation of ERK accelerates repair of renal tubular epithelial
cells, whereas it inhibits progression of fibrosis following ischemia/reperfusion injury. Biochim Biophys Acta 1832: 1998–2008,
2013. doi:10.1016/j.bbadis.2013.07.001.
Lin AW, Barradas M, Stone JC, Aelst L, Serrano M, Lowe SW.
Premature senescence involving p53 and p16 is activated in
response to constitutive MEK/MAPK mitogenic signaling. Genes Dev
12: 3008–3019, 1998. doi:10.1101/gad.12.19.3008.
Arbel-Goren R, Levy Y, Ronen D, Zick Y. Cyclin-dependent kinase
inhibitors and JNK act as molecular switches, regulating the choice
between growth arrest and apoptosis induced by galectin-8. J Biol
Chem 280: 19105–19114, 2005. doi:10.1074/jbc.M502060200.
Iwasa H, Han J, Ishikawa F. Mitogen-activated protein kinase p38
defines the common senescence-signalling pathway. Genes Cells 8:
131–144, 2003. doi:10.1046/j.1365-2443.2003.00620.x.
Chibaya L, Karim B, Zhang H, Jones SN. Mdm2 phosphorylation by
Akt regulates the p53 response to oxidative stress to promote cell
proliferation and tumorigenesis. Proc Natl Acad Sci USA 118:
e2003193118, 2021. doi:10.1073/pnas.2003193118.
Liguori I, Russo G, Curcio F, Bulli G, Aran L, Della-Morte D,
Gargiulo G, Testa G, Cacciatore F, Bonaduce D, Abete P. Oxidative
stress, aging, and diseases. Clin Interv Aging 13: 757–772, 2018.
doi:10.2147/CIA.S158513.
Xing L, Guo H, Meng S, Zhu B, Fang J, Huang J, Chen J, Wang Y,
Wang L, Yao X, Wang H. Klotho ameliorates diabetic nephropathy
by activating Nrf2 signaling pathway in podocytes. Biochem Biophys
Res Commun 534: 450–456, 2021. doi:10.1016/j.bbrc.2020.11.061.
Yamamoto M, Clark JD, Pastor JV, Gurnani P, Nandi A, Kurosu
H, Miyoshi M, Ogawa Y, Castrillon DH, Rosenblatt KP, Kuro-O
M. Regulation of oxidative stress by the anti-aging hormone
Klotho. J Biol Chem 280: 38029–38034, 2005. doi:10.1074/jbc.
M509039200.
Jiang F, Liu GS, Dusting GJ, Chan EC. NADPH oxidase-dependent
redox signaling in TGF-b-mediated fibrotic responses. Redox Biol 2:
267–272, 2014. doi:10.1016/j.redox.2014.01.012.
Gaitanaki C, Konstantina S, Chrysa S, Beis I. Oxidative stress stimulates multiple MAPK signalling pathways and phosphorylation of the
small HSP27 in the perfused amphibian heart. J Exp Biol 206: 2759–
2769, 2003. doi:10.1242/jeb.00483.
loën A, Even
Holzenberger M, Dupont J, Ducos B, Leneuve P, Ge
PC, Cervera P, Bouc YL. IGF-1 receptor regulates lifespan and resistance to oxidative stress in mice. Nature 421: 182–187, 2003.
doi:10.1038/nature01298.
AJP-Renal Physiol doi:10.1152/ajprenal.00609.2020 www.ajprenal.org
Downloaded from journals.physiology.org/journal/ajprenal at Hiroshima Daigaku (133.041.093.090) on November 29, 2021.
F811
...