Association Between Nrf2 and CDKN2A Expression in Patients with End-stage Renal Disease: a Pilot Study

Overview

Journal Aging (Albany NY)

Specialty Geriatrics

Date 2020 Jul 15

PMID 32661200

Citations 4

Authors

Keiichi Sumida

Zhongji Han

Ankur A Dashputre

Praveen K Potukuchi

Csaba P Kovesdy

Affiliations

Soon will be listed here.

Abstract

Patients with end-stage renal disease (ESRD) display phenotypic features of premature biological aging, characterized by disproportionately high morbidity and mortality at a younger age. Nuclear factor erythroid 2-related factor 2 (Nrf2) activity, a master regulator of antioxidative responses, declines with age and is implicated in the pathogenesis of age-related disorders; however, little is known about the association between Nrf2 and premature biological aging in ESRD patients. In a cross-sectional pilot cohort of 34 ESRD patients receiving maintenance hemodialysis, we measured the expression of Nrf2 and cyclin-dependent kinase inhibitor 2A (CDKN2A, or p16, a biomarker of biological aging) genes in whole blood and examined the association of Nrf2 with CDKN2A expression, using Spearman's rank correlation and multivariable linear regression models with adjustment for potential confounders. There was a significant negative correlation between Nrf2 and CDKN2A expression (rho=-0.51, =0.002); while no significant correlation was found between Nrf2 expression and chronological age (rho=-0.02, =0.91). After multivariable adjustment, Nrf2 expression remained significantly and negatively associated with CDKN2A expression ( coefficient=-1.51, =0.01), independent of chronological age, gender, race, and diabetes status. These findings suggest a potential contribution of Nrf2 dysfunction to the development of premature biological aging and its related morbidities in ESRD patients.

Citing Articles

Circulating microRNA Profiles for Premature Cardiovascular Death in Patients with Kidney Failure with Replacement Therapy.

Kuscu C, Mallisetty Y, Naik S, Han Z, Berta C, Kuscu C J Clin Med. 2023; 12(15).

PMID: 37568412 PMC: 10419472. DOI: 10.3390/jcm12155010.

Association of DNA methylation signatures with premature ageing and cardiovascular death in patients with end-stage kidney disease: a pilot epigenome-wide association study.

Sumida K, Mozhui K, Liang X, Mallisetty Y, Han Z, Kovesdy C Epigenetics. 2023; 18(1):2214394.

PMID: 37207321 PMC: 10202091. DOI: 10.1080/15592294.2023.2214394.

Circulating Microbiota in Cardiometabolic Disease.

Sumida K, Han Z, Chiu C, Mims T, Bajwa A, Demmer R Front Cell Infect Microbiol. 2022; 12:892232.

PMID: 35592652 PMC: 9110890. DOI: 10.3389/fcimb.2022.892232.

Circulating Microbial Signatures and Cardiovascular Death in Patients With ESRD.

Sumida K, Pierre J, Han Z, Mims T, Potukuchi P, Yuzefpolskaya M Kidney Int Rep. 2021; 6(10):2617-2628.

PMID: 34622101 PMC: 8484116. DOI: 10.1016/j.ekir.2021.07.023.

References

Foley R, Parfrey P, Sarnak M . Clinical epidemiology of cardiovascular disease in chronic renal disease. Am J Kidney Dis. 1998; 32(5 Suppl 3):S112-9. DOI: 10.1053/ajkd.1998.v32.pm9820470. View

Leurs P, Lindholm B, Stenvinkel P . Effects of hemodiafiltration on uremic inflammation. Blood Purif. 2013; 35 Suppl 1:11-7. DOI: 10.1159/000346359. View

Go A, Chertow G, Fan D, McCulloch C, Hsu C . Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization. N Engl J Med. 2004; 351(13):1296-305. DOI: 10.1056/NEJMoa041031. View

Cardozo L, Pedruzzi L, Stenvinkel P, Stockler-Pinto M, Daleprane J, Leite Jr M . Nutritional strategies to modulate inflammation and oxidative stress pathways via activation of the master antioxidant switch Nrf2. Biochimie. 2013; 95(8):1525-33. DOI: 10.1016/j.biochi.2013.04.012. View

Schmidlin C, Dodson M, Madhavan L, Zhang D . Redox regulation by NRF2 in aging and disease. Free Radic Biol Med. 2019; 134:702-707. PMC: 6588470. DOI: 10.1016/j.freeradbiomed.2019.01.016. View

Choi B, Kang K, Kwak M . Effect of redox modulating NRF2 activators on chronic kidney disease. Molecules. 2014; 19(8):12727-59. PMC: 6271622. DOI: 10.3390/molecules190812727. View

Sturmlechner I, Durik M, Sieben C, Baker D, van Deursen J . Cellular senescence in renal ageing and disease. Nat Rev Nephrol. 2016; 13(2):77-89. DOI: 10.1038/nrneph.2016.183. View

McGlynn L, Stevenson K, Lamb K, Zino S, Brown M, Prina A . Cellular senescence in pretransplant renal biopsies predicts postoperative organ function. Aging Cell. 2008; 8(1):45-51. DOI: 10.1111/j.1474-9726.2008.00447.x. View

Duan W, Zhang R, Guo Y, Jiang Y, Huang Y, Jiang H . Nrf2 activity is lost in the spinal cord and its astrocytes of aged mice. In Vitro Cell Dev Biol Anim. 2009; 45(7):388-97. DOI: 10.1007/s11626-009-9194-5. View

10.

Baker D, Childs B, Durik M, Wijers M, Sieben C, Zhong J . Naturally occurring p16(Ink4a)-positive cells shorten healthy lifespan. Nature. 2016; 530(7589):184-9. PMC: 4845101. DOI: 10.1038/nature16932. View

11.

Pedruzzi L, Cardozo L, Daleprane J, Stockler-Pinto M, Monteiro E, Leite Jr M . Systemic inflammation and oxidative stress in hemodialysis patients are associated with down-regulation of Nrf2. J Nephrol. 2015; 28(4):495-501. DOI: 10.1007/s40620-014-0162-0. View

12.

Harman D . Aging: a theory based on free radical and radiation chemistry. J Gerontol. 1956; 11(3):298-300. DOI: 10.1093/geronj/11.3.298. View

13.

Janic M, Lunder M, Novakovic S, Skerl P, Sabovic M . Expression of Longevity Genes Induced by a Low-Dose Fluvastatin and Valsartan Combination with the Potential to Prevent/Treat "Aging-Related Disorders". Int J Mol Sci. 2019; 20(8). PMC: 6514706. DOI: 10.3390/ijms20081844. View

14.

Borges N, Barros A, Nakao L, Dolenga C, Fouque D, Mafra D . Protein-Bound Uremic Toxins from Gut Microbiota and Inflammatory Markers in Chronic Kidney Disease. J Ren Nutr. 2016; 26(6):396-400. DOI: 10.1053/j.jrn.2016.07.005. View

15.

Gingell-Littlejohn M, McGuinness D, McGlynn L, Kingsmore D, Stevenson K, Koppelstaetter C . Pre-transplant CDKN2A expression in kidney biopsies predicts renal function and is a future component of donor scoring criteria. PLoS One. 2013; 8(7):e68133. PMC: 3701657. DOI: 10.1371/journal.pone.0068133. View

16.

Slocum S, Kensler T . Nrf2: control of sensitivity to carcinogens. Arch Toxicol. 2011; 85(4):273-84. DOI: 10.1007/s00204-011-0675-4. View

17.

Stockler-Pinto M, Soulage C, Borges N, Cardozo L, Dolenga C, Nakao L . From bench to the hemodialysis clinic: protein-bound uremic toxins modulate NF-κB/Nrf2 expression. Int Urol Nephrol. 2017; 50(2):347-354. DOI: 10.1007/s11255-017-1748-y. View

18.

Lopez-Otin C, Blasco M, Partridge L, Serrano M, Kroemer G . The hallmarks of aging. Cell. 2013; 153(6):1194-217. PMC: 3836174. DOI: 10.1016/j.cell.2013.05.039. View

19.

Sawicka-Gutaj N, Waligorska-Stachura J, Andrusiewicz M, Biczysko M, Sowinski J, Skrobisz J . Nicotinamide phosphorybosiltransferase overexpression in thyroid malignancies and its correlation with tumor stage and with survivin/survivin DEx3 expression. Tumour Biol. 2015; 36(10):7859-63. PMC: 4605962. DOI: 10.1007/s13277-015-3506-z. View

20.

Ungvari Z, Bailey-Downs L, Sosnowska D, Gautam T, Koncz P, Losonczy G . Vascular oxidative stress in aging: a homeostatic failure due to dysregulation of NRF2-mediated antioxidant response. Am J Physiol Heart Circ Physiol. 2011; 301(2):H363-72. PMC: 3154665. DOI: 10.1152/ajpheart.01134.2010. View