Abstract
Cerebral ischemic preconditioning (CIP)-induced brain ischemic tolerance protects neurons from subsequent lethal ischemic insult. However, the specific mechanisms underlying CIP remain unclear. In the present study, we explored the hypothesis that peroxisome proliferator-activated receptor gamma (PPARγ) participates in the upregulation of Klotho during the induction of brain ischemic tolerance by CIP. First we investigated the expression of Klotho during the brain ischemic tolerance induced by CIP. Lethal ischemia significantly decreased Klotho expression from 6 h to 7 days, while CIP significantly increased Klotho expression from 12 h to 7 days in the hippocampal CA1 region. Inhibition of Klotho expression by its shRNA blocked the neuroprotection induced by CIP. These results indicate that Klotho participates in brain ischemic tolerance by CIP. Furthermore, we tested the role of PPARγ in regulating Klotho expression after CIP. CIP caused PPARγ protein translocation to the nucleus in neurons in the CA1 region of the hippocampus. Pretreatment with GW9962, a PPARγ inhibitor, significantly attenuated the upregulation of Klotho protein and blocked the brain ischemic tolerance induced by CIP. Taken together, it can be concluded that Klotho upregulation via PPARγ contributes to the induction of brain ischemic tolerance by CIP.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
Data Availability
The data used in the present study are available from the corresponding author on reasonable request.
Abbreviations
- BCCAs:
-
Bilateral common carotid arteries
- CIP:
-
Cerebral ischemic preconditioning for 3 min
- d:
-
Day
- h:
-
Hour
- i.c.v.:
-
Intracerebroventricular injection
- II:
-
Ischemic insult for 8 min
- KL:
-
Klotho
- min:
-
Minute
- PPARγ:
-
Peroxisome proliferator-activated receptor gamma
References
Badhwar A, Brown R, Stanimirovic DB, Haqqani AS, Hamel E (2017) Proteomic differences in brain vessels of Alzheimer’s disease mice: normalization by PPARgamma agonist pioglitazone. J Cereb Blood Flow Metab 37(3):1120–1136. https://doi.org/10.1177/0271678X16655172
Behera R, Kaur A, Webster MR, Kim S, Ndoye A, Kugel CH, Alicea GM, Wang J, Ghosh K, Cheng P, Lisanti S, Marchbank K, Dang V, Levesque M, Dummer R, Xu X, Herlyn M, Aplin AE, Roesch A, Caino C, Altieri DC, Weeraratna AT (2017) Inhibition of age-related therapy resistance in melanoma by rosiglitazone-mediated induction of Klotho. Clin Cancer Res 23(12):3181–3190. https://doi.org/10.1158/1078-0432.CCR-17-0201
Chen CD, Sloane JA, Li H, Aytan N, Giannaris EL, Zeldich E, Hinman JD, Dedeoglu A, Rosene DL, Bansal R, Luebke JI, Kuro-o M, Abraham CR (2013) The antiaging protein Klotho enhances oligodendrocyte maturation and myelination of the CNS. J Neurosci 33(5):1927–1939. https://doi.org/10.1523/JNEUROSCI.2080-12.2013
Collino M, Patel NS, Lawrence KM, Collin M, Latchman DS, Yaqoob MM, Thiemermann C (2005) The selective PPARgamma antagonist GW9662 reverses the protection of LPS in a model of renal ischemia-reperfusion. Kidney Int 68(2):529–536
Dentesano G, Serratosa J, Tusell J, Ramón P, Valente T, Saura J, Solà C (2014) CD200R1 and CD200 expression are regulated by PPAR-γ in activated glial cells. Glia 62(6):982–998. https://doi.org/10.1002/glia.22656
Ding L, Zhou J, Ye L, Sun Y, Jiang Z, Gan D, Xu L, Luo Q, Wang G (2020) PPAR-γ is critical for HDAC3-mediated control of oligodendrocyte progenitor cell proliferation and differentiation after focal demyelination. Mol Neurobiol. https://doi.org/10.1007/s12035-020-02060-8
Emami Aleagha MS, Siroos B, Ahmadi M, Balood M, Palangi A, Haghighi AN, Harirchian MH (2015) Decreased concentration of Klotho in the cerebrospinal fluid of patients with relapsing-remitting multiple sclerosis. J Neuroimmunol 281:5–8. https://doi.org/10.1016/j.jneuroim.2015.02.004
Garrido-Gil P, Joglar B, Rodriguez-Perez AI, Guerra MJ, Labandeira-Garcia JL (2012) Involvement of PPAR-γ in the neuroprotective and anti-inflammatory effects of angiotensin type 1 receptor inhibition: effects of the receptor antagonist telmisartan and receptor deletion in a mouse MPTP model of Parkinson’s disease. J Neuroinflammation 9:38. https://doi.org/10.1186/1742-2094-9-38
Giampietro L, Gallorini M, De Filippis B, Amoroso R, Cataldi A, di Giacomo V (2019) PPAR-γ agonist GL516 reduces oxidative stress and apoptosis occurrence in a rat astrocyte cell line. Neurochem Int 126:239–245. https://doi.org/10.1016/j.neuint.2019.03.021
Jin J, Albertz J, Guo Z, Peng Q, Rudow G, Troncoso J, Ross CA, Duan W (2013) Neuroprotective effects of PPAR-γ agonist rosiglitazone in N171–82Q mouse model of Huntington’s disease. J Neurochem 125(3):410–419. https://doi.org/10.1111/jnc.12190
Kato H, Liu Y, Araki T, Kogure K (1991) Temporal profile of the effects of pretreatment with brief cerebral ischemia on the neuronal damage following secondary ischemic insult in the gerbil: cumulative damage and protective effects. Brain Res 553(2):238–242. https://doi.org/10.1016/0006-8993(91)90831-f
Kitagawa K, Matsumoto M, Tagaya M, Hata R, Ueda H, Niinobe M, Handa N, Fukunaga R, Kimura K, Mikoshiba K et al (1990) “Ischemic tolerance” phenomenon found in the brain. Brain Res 528(1):21–24. https://doi.org/10.1016/0006-8993(90)90189-i
Kuang X, Chen YS, Wang LF, Li YJ, Liu K, Zhang MX, Li LJ, Chen C, He Q, Wang Y, Du JR (2014) Klotho upregulation contributes to the neuroprotection of ligustilide in an Alzheimer’s disease mouse model. Neurobiol Aging 35(1):169–178. https://doi.org/10.1016/j.neurobiolaging.2013.07.019
Lee J, Woo H, Chang Y, Jin Y, Jo I, Kim J, Song TJ (2019) Plasma Klotho concentrations predict functional outcome at three months after acute ischemic stroke patients. Ann Med 51:262–269. https://doi.org/10.1080/07853890.2019.1617434
Li D, Jing D, Liu Z, Chen Y, Huang F, Behnisch T (2019) Enhanced expression of secreted alpha-Klotho in the hippocampus alters nesting behavior and memory formation in mice. Front Cell Neurosci 13:133. https://doi.org/10.3389/fncel.2019.00133
Lim K, Groen A, Molostvov G, Lu T, Lilley KS, Snead D, James S, Wilkinson IB, Ting S, Hsiao L-L, Hiemstra TF, Zehnder D (2015) α-Klotho expression in human tissues. J Clin Endocrinol Metab 100(10):E1308–E1318. https://doi.org/10.1210/jc.2015-1800
Lin W, Zhang Q, Liu L, Yin S, Liu Z, Cao W (2017a) Klotho restoration via acetylation of peroxisome proliferation-activated receptor gamma reduces the progression of chronic kidney disease. Kidney Int 92(3):669–679. https://doi.org/10.1016/j.kint.2017.02.023
Lin W, Zhang Q, Liu L, Yin S, Liu Z, Cao W (2017b) Klotho restoration via acetylation of peroxisome proliferation-activated receptor γ reduces the progression of chronic kidney disease. Kidney Int 92(3):669–679. https://doi.org/10.1016/j.kint.2017.02.023
Liu YX, Zhang M, Liu LZ, Cui X, Hu YY, Li WB (2012) The role of glutamate transporter-1a in the induction of brain ischemic tolerance in rats. Glia 60(1):112–124. https://doi.org/10.1002/glia.21252
Liu H, Rose ME, Culver S, Ma X, Dixon CE, Graham SH (2016) Rosiglitazone attenuates inflammation and CA3 neuronal loss following traumatic brain injury in rats. Biochem Biophys Res Commun 472(4):648–655. https://doi.org/10.1016/j.bbrc.2016.03.003
Liu L, Liu Y, Zhang Y, Bi X, Nie L, Liu C, Xiong J, He T, Xu X, Yu Y, Yang K, Gu J, Huang Y, Zhang J, Zhang Z, Zhang B, Zhao J (2018) High phosphate-induced downregulation of PPARgamma contributes to CKD-associated vascular calcification. J Mol Cell Cardiol 114:264–275. https://doi.org/10.1016/j.yjmcc.2017.11.021
Long F-Y, Shi MQ, Zhou HJ, Liu DL, Sang NDuJR (2018a) Klotho upregulation contributes to the neuroprotection of ligustilide against cerebral ischemic injury in mice. Eur J Pharmacol 820:198–205. https://doi.org/10.1016/j.ejphar.2017.12.019
Long F, Shi M, Zhou H, Liu D, Sang N, Du JR (2018b) Klotho upregulation contributes to the neuroprotection of ligustilide against cerebral ischemic injury in mice. Eur J Pharmacol 820:198–205. https://doi.org/10.1016/j.ejphar.2017.12.019
Narayanan SV, Dave KR, Perez-Pinzon MA (2018) Ischemic preconditioning protects astrocytes against oxygen glucose deprivation via the nuclear erythroid 2-related factor 2 pathway. Transl Stroke Res 9(2):99–109. https://doi.org/10.1007/s12975-017-0574-y
Pulsinelli WA, Brierley JB (1979) A new model of bilateral hemispheric ischemia in the unanesthetized rat. Stroke 10(3):267–272
Salech F, Varela-Nallar L, Arredondo SB, Bustamante DB, Andaur GA, Cisneros R, Ponce DP, Ayala P, Inestrosa NC, Valdes JL et al (2019) Local Klotho enhances neuronal progenitor proliferation in the adult hippocampus. J Gerontol A Biol Sci Med Sci 74(7):1043–1051. https://doi.org/10.1093/gerona/glx248
Wang X, Li R, Wang X, Fu Q, Ma S (2015) Umbelliferone ameliorates cerebral ischemia-reperfusion injury via upregulating the PPAR gamma expression and suppressing TXNIP/NLRP3 inflammasome. Neurosci Lett 600:182–187. https://doi.org/10.1016/j.neulet.2015.06.016
Wnuk A, Przepiórska K, Pietrzak BA, Kajta M (2021) Post-treatment with amorfrutin B Evokes PPARγ-mediated neuroprotection against hypoxia and ischemia. Biomedicines. https://doi.org/10.3390/biomedicines9080854
Wu J, Kao M, Tsai H, Cheung W, Chen J, Ong W, Sun G, Lin TN (2018) Clinacanthus nutans mitigates neuronal apoptosis and ischemic brain damage through augmenting the C/EBPβ-driven PPAR-γ transcription. Mol Neurobiol 55(7):5425–5438. https://doi.org/10.1007/s12035-017-0776-z
Xing L, Fang J, Zhu B, Wang L, Chen J, Wang Y, Huang J, Wang H, Yao X (2021) Astragaloside IV protects against podocyte apoptosis by inhibiting oxidative stress via activating PPARgamma-Klotho-FoxO1 axis in diabetic nephropathy. Life Sci 269:119068. https://doi.org/10.1016/j.lfs.2021.119068
Xu L, Cao H, Xie Y, Zhang Y, Du M, Xu X, Ye R, Liu X (2019) Exosome-shuttled miR-92b-3p from ischemic preconditioned astrocytes protects neurons against oxygen and glucose deprivation. Brain Res 1717:66–73. https://doi.org/10.1016/j.brainres.2019.04.009
Yang HC, Deleuze S, Zuo Y, Potthoff SA, Ma LJ, Fogo AB (2009) The PPARgamma agonist pioglitazone ameliorates aging-related progressive renal injury. J Am Soc Nephrol 20(11):2380–2388. https://doi.org/10.1681/asn.2008111138
Yang T, Sun Y, Li Q, Li S, Shi Y, Leak R, Chen J, Zhang F (2020) Ischemic preconditioning provides long-lasting neuroprotection against ischemic stroke: the role of Nrf2. Exp Neurol 325:113142. https://doi.org/10.1016/j.expneurol.2019.113142
Zhang H, Li Y, Fan Y, Wu J, Zhao B, Guan Y, Chien S, Wang N (2008) Klotho is a target gene of PPAR-gamma. Kidney Int 74(6):732–739. https://doi.org/10.1038/ki.2008.244
Zhang M, Gong JX, Wang JL, Jiang MY, Li L, Hu YY, Qi J, Zhang LY, Zhao H, Cui X, Xian XH, Li WB (2017) p38 MAPK participates in the mediation of GLT-1 Up-regulation during the induction of brain ischemic tolerance by cerebral ischemic preconditioning. Mol Neurobiol 54(1):58–71. https://doi.org/10.1007/s12035-015-9652-x
Zhang LS, Liu Y, Chen Y, Ren JL, Zhang YR, Yu YR, Jia MZ, Ning ZP, Du J, Tang CS, Qi YF (2020a) Intermedin alleviates pathological cardiac remodeling by upregulating klotho. Pharmacol Res 159:104926. https://doi.org/10.1016/j.phrs.2020.104926
Zhang S, Xu M, Liu Z-J, Feng J, Ma Y (2020b) Neuropsychiatric issues after stroke: Clinical significance and therapeutic implications. World J Psychiatr 10(6):125–138. https://doi.org/10.5498/wjp.v10.i6.125
Zhao CC, Jiang MY, Zhang LY, Hu YY, Hu ZJ, Zhang MY, Qi J, Su AC, Lou N, Xian XH, Zhang JG, Li WB, Zhang M (2019) Peroxisome proliferator-activated receptor gamma participates in the acquisition of brain ischemic tolerance induced by ischemic preconditioning via glial glutamate transporter 1 in vivo and in vitro. J Neurochem 151(5):608–625. https://doi.org/10.1111/jnc.14824
Zhao Y, Zeng CY, Li XH, Yang TT, Kuang X, Du JR (2020) Klotho overexpression improves amyloid-β clearance and cognition in the APP/PS1 mouse model of Alzheimer’s disease. Aging Cell. https://doi.org/10.1111/acel.13239
Zhou HJ, Li H, Shi MQ, Mao XN, Liu DL, Chang YR, Gan YM, Kuang XDuJR (2017) Protective effect of Klotho against ischemic brain injury is associated with inhibition of RIG-I/NF-kappaB signaling. Front Pharmacol 8:950. https://doi.org/10.3389/fphar.2017.00950
Zimmermann M, Köhler L, Kovarova M, Lerche S, Schulte C, Wurster I, Machetanz G, Deuschle C, Hauser AK, Gasser T, Berg D, Schleicher E, Maetzler WBrockmann K, (2021) The longevity gene Klotho and its cerebrospinal fluid protein profiles as a modifier for Parkinson´s disease. Eur J Neurol 28(5):1557–1565. https://doi.org/10.1111/ene.14733
Acknowledgements
This work was supported by the Natural Science Foundation of Hebei Province (Nos. H2021206160, H2022206579) and the National Natural Science Foundation of China (No. 81971228).
Funding
Innovative Research Group Project of the National Natural Science Foundation of China,81771253,Min Zhang,81971228,Min Zhang,Natural Science Foundation of Hebei Province,H201906702,Min Zhang,the Natural Science Foundation of Hebei Province,H2021206160,Min Zhang
Author information
Authors and Affiliations
Contributions
LYZ, XYL and ACS performed the experiments. LYZ and XYL analyzed the data and drafted the manuscript. YYH and XHX drafted the figures. MZ, JGZ and WBL designed the study and contributed to editing the final draft. All authors read and approved the final manuscript.
Corresponding author
Ethics declarations
Conflict of interest
The authors declare no potential conflicts of interest.
Ethical Approval
All animals in this study were approved by the Laboratory Animal Ethical and Welfare Committee of Hebei Medical University, China (Approval No. IACUC-Hebmu–2020013).
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary Information
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
Cite this article
Zhang, LY., Liu, XY., Su, Ac. et al. Klotho Upregulation via PPARγ Contributes to the Induction of Brain Ischemic Tolerance by Cerebral Ischemic Preconditioning in Rats. Cell Mol Neurobiol 43, 1355–1367 (2023). https://doi.org/10.1007/s10571-022-01255-y
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10571-022-01255-y