Abstract
Background and Aims
The predominant distribution of the antiaging Klotho protein in both the kidneys and brain may point to its essential role in protecting against dysfunction of the kidney-brain axis during the aging process. Our previous study showed that the downregulation of Klotho was involved in aging-related cognitive impairment in aged senescence-accelerated mouse prone-8 (SAMP8) mice. The present study investigated the potential role of Klotho in aging-associated inflammation and renal injury.
Methods
Age- and gender-matched groups of SAMP8 mice and their corresponding normal control senescence-accelerated mouse resistant-1 (SAMR1) were used to investigate the potential role of Klotho in aging-associated inflammation and renal injury.
Results
Compared with aged SAMR1 controls, early-stage chronic kidney disease (CKD), which is associated with an increase in the urinary albumin-to-creatinine ratio, inflammatory cell infiltration, glomerulosclerosis, and tubulointerstitial fibrosis, was observed in aged SAMP8 mice. Furthermore, the aging-related loss of Klotho-induced activation of the retinoic acid-inducible gene 1/nuclear factor-κB (RIG-I/NF-κB) signaling pathway and subsequent production of the proinflammatory mediators tumor necrosis factor α, interleukin-6, and inducible nitric oxide synthase in the kidneys of aged SAMP8 mice compared with SAMR1 controls.
Conclusions
The present results suggest that aging-related inflammation and the development of early-stage CKD are likely associated with the downregulation of Klotho and induction of the RIG-I/NF-κB signaling pathway in 12-month-old SAMP8 mice. Moreover, aged SAMP8 mice with cognitive deficits and renal damage may be a potential mouse model for investigating the kidney-brain axis in the aging process.
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References
Campbell KH, O’Hare AM (2008) Kidney disease in the elderly: update on recent literature. Curr Opin Nephrol Hypertens 17(3):298–303
Drew DA, Weiner DE (2014) Cognitive impairment in chronic kidney disease: keep vascular disease in mind. Kidney Int 85:505–507
Bugnicourt JM, Godefroy O, Chillon JM et al (2013) Cognitive disorders and dementia in CKD: the neglected kidney-brain axis. J Am Soc Nephrol 24:353–363
Zuo Z, Lei H, Wang X et al (2011) Aging-related kidney damage is associated with a decrease in klotho expression and an increase in superoxide production. Age (Dordr) 33:261–274
Kuang X, Chen YS, Wang LF et al (2014) Klotho upregulation contributes to the neuroprotection of ligustilide in an Alzheimer’s disease mouse model. Neurobiol Aging 35:169–178
Kuro-o M, Matsumura Y, Aizawa H et al (1997) Mutation of the mouse klotho gene leads to a syndrome resembling ageing. Nature 390:45–51
Mitobe M, Yoshida T, Sugiura H et al (2005) Oxidative stress decreases klotho expression in a mouse kidney cell line. Nephron Exp Nephrol 101:e67–e74
Kurosu H, Yamamoto M, Clark JD et al (2005) Suppression of aging in mice by the hormone Klotho. Science 309:1829–1833
Liu F, Wu S, Ren H et al (2011) Klotho suppresses RIG-I-mediated senescence-associated inflammation. Nat Cell Biol 13:254–262
Zeldich E, Chen CD, Colvin TA et al (2014) D.A. Harris, C.R. Abraham, The neuroprotective effect of Klotho is mediated via regulation of members of the redox system. J Biol Chem 289:24700–24715
Koh N, Fujimori T, Nishiguchi S et al (2001) Severely reduced production of klotho in human chronic renal failure kidney. Biochem Biophys Res Commun 280:1015–1020
Semba RD, Moghekar AR, Hu J et al (2014) Klotho in the cerebrospinal fluid of adults with and without Alzheimer’s disease. Neurosci Lett 558:37–40
Morley JE, Armbrecht HJ, Farr SA et al (2012) The senescence accelerated mouse (SAMP8) as a model for oxidative stress and Alzheimer’s disease. Biochim Biophys Acta 1822:650–656
Baltanas A, Solesio ME, Zalba G et al (2013) The senescence-accelerated mouse prone-8 (SAM-P8) oxidative stress is associated with upregulation of renal NADPH oxidase system. J Physiol Biochem 69:927–935
Shi XY (2008) Protective effects of Ginsenoside Rb1/Rg1 on aging kidney of senescence accelerated mouse/prone 8. The affiliated Union Hospital of Fujian Medical University, Fuzhou
Tsaih SW, Pezzolesi MG, Yuan R et al (2010) Genetic analysis of albuminuria in aging mice and concordance with loci for human diabetic nephropathy found in a genome-wide association scan. Kidney Int 77:201–210
Lim JH, Kim EN, Kim MY et al (2012) Age-associated molecular changes in the kidney in aged mice. Oxid Med Cell Longev 2012:171383
Yu L, Chen C, Wang LF et al (2013) Neuroprotective effect of kaempferol glycosides against brain injury and neuroinflammation by inhibiting the activation of NF-kappaB and STAT3 in transient focal stroke. PLoS ONE 8:e55839
Tesch GH (2010) Review: serum and urine biomarkers of kidney disease: A pathophysiological perspective. Nephrology (Carlton) 15:609–616
Flood JF, Morley JE (1998) Learning and memory in the SAMP8 mouse. Neurosci Biobehav Rev 22:1–20
Hu MC, Kuro-o M, Moe OW (2012) Secreted klotho and chronic kidney disease. Adv Exp Med Biol 728:126–157
Song JH, Lee MY, Kim YJ et al (2014) Developmental immunolocalization of the Klotho protein in mouse kidney epithelial cells. Eur J Histochem 58:2256
Izquierdo MC, Perez-Gomez MV, Sanchez-Niño MD et al (2012) Klotho, phosphate and inflammation/ageing in chronic kidney disease. Nephrol Dial Transplant 27:iv6–iv10
Poeck H, Bscheider M, Gross O et al (2010) Recognition of RNA virus by RIG-I results in activation of CARD9 and inflammasome signaling for interleukin 1 beta production. Nat Immunol 11:63–69
Acknowledgments
This work was supported by the National Science Foundation of China (81473219).
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On behalf of all authors, the corresponding author states that there is no conflict of interest.
Human and Animal Rights
All of the animal procedures were performed according to China Animal Welfare Legislation and the Guidelines of Laboratory Animal Care and Use of Sichuan University.
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All participants signed an informed consent form prior to their inclusion in the study.
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40520_2015_371_MOESM1_ESM.tif
Supplementary material 1 (TIFF 39728 kb) Fig. S1. Immunohistochemical staining of renal Klotho expression in C57BL/6 mice. Representative images show Klotho immunoreactivity in the renal cortex and medulla in 15-week-old male C57BL/6 mice
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Zeng, Y., Wang, PH., Zhang, M. et al. Aging-related renal injury and inflammation are associated with downregulation of Klotho and induction of RIG-I/NF-κB signaling pathway in senescence-accelerated mice. Aging Clin Exp Res 28, 69–76 (2016). https://doi.org/10.1007/s40520-015-0371-y
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DOI: https://doi.org/10.1007/s40520-015-0371-y