The Regulatory Effects of JAK2/STAT3 on Spermatogenesis and the Redox Keap1/Nrf2 Axis in an Animal Model of Testicular Ischemia Reperfusion Injury

Overview

Journal Cells

Publisher MDPI

Specialties Biochemistry
Biophysics
Cell Biology
Molecular Biology

Date 2023 Sep 28

PMID 37759514

Authors

Abdullah Alnajem

May Al-Maghrebi

Affiliations

Soon will be listed here.

Abstract

The male reproductive system requires the pleiotropic activity of JAK/STAT to maintain its function, especially spermatogenesis. The study aims to investigate the effect of JAK2 signaling on the expression of the Keap1/Nrf2 axis, spermatogenesis, and the Sertoli cells (Sc) junctions in an animal model of testicular ischemia reperfusion injury (tIRI). Testes subjected to tIRI exhibited increased JAK2/STAT3 activity associated with spermatogenic arrest and reduced expression of the Sc junctions. In addition, there was an increased protein expression of Keap1 and decreased Nrf2., which was coupled with the downregulation of gene expression of antioxidant enzymes. Reduced SOD and CAT activities were accompanied by increased lipid peroxidation and protein carbonylation during tIRI. Increased caspase 9 activity and / ratio indicated initiation of apoptosis. Inhibition of JAK2 activity by AG490 maintained the integrity of spermatogenesis and SC junctions, normalized the expression of the Keap1/Nrf2 axis and its downstream antioxidant enzymes, and prevented germ cell apoptosis. The results further emphasized the regulatory role of JAK2/STAT3 on spermatogenesis, Keap1/Nrf2 signaling, and maintenance of the testicular redox balance to combat testicular dysfunction and male infertility.

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References

Gow A, Southwood C, Li J, Pariali M, Riordan G, Brodie S . CNS myelin and sertoli cell tight junction strands are absent in Osp/claudin-11 null mice. Cell. 1999; 99(6):649-59. DOI: 10.1016/s0092-8674(00)81553-6. View

Khashab F, Al-Saleh F, Al-Kandari N, Fadel F, Al-Maghrebi M . JAK Inhibition Prevents DNA Damage and Apoptosis in Testicular Ischemia-Reperfusion Injury via Modulation of the ATM/ATR/Chk Pathway. Int J Mol Sci. 2021; 22(24). PMC: 8706947. DOI: 10.3390/ijms222413390. View

Jiang X, Bukhari I, Zheng W, Yin S, Wang Z, Cooke H . Blood-testis barrier and spermatogenesis: lessons from genetically-modified mice. Asian J Androl. 2014; 16(4):572-80. PMC: 4104086. DOI: 10.4103/1008-682X.125401. View

Lachance C, Leclerc P . Mediators of the Jak/STAT signaling pathway in human spermatozoa. Biol Reprod. 2011; 85(6):1222-31. PMC: 4480430. DOI: 10.1095/biolreprod.111.092379. View

Hu X, Li J, Fu M, Zhao X, Wang W . The JAK/STAT signaling pathway: from bench to clinic. Signal Transduct Target Ther. 2021; 6(1):402. PMC: 8617206. DOI: 10.1038/s41392-021-00791-1. View

Celino F, Yamaguchi S, Miura C, Ohta T, Tozawa Y, Iwai T . Tolerance of spermatogonia to oxidative stress is due to high levels of Zn and Cu/Zn superoxide dismutase. PLoS One. 2011; 6(2):e16938. PMC: 3041797. DOI: 10.1371/journal.pone.0016938. View

DCruz O, Vassilev A, Uckun F . Members of the Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathway are present and active in human sperm. Fertil Steril. 2001; 76(2):258-66. DOI: 10.1016/s0015-0282(01)01896-9. View

Tonelli C, Chio I, Tuveson D . Transcriptional Regulation by Nrf2. Antioxid Redox Signal. 2017; 29(17):1727-1745. PMC: 6208165. DOI: 10.1089/ars.2017.7342. View

Hayes J, Dinkova-Kostova A . The Nrf2 regulatory network provides an interface between redox and intermediary metabolism. Trends Biochem Sci. 2014; 39(4):199-218. DOI: 10.1016/j.tibs.2014.02.002. View

10.

Niture S, Jaiswal A . Nrf2-induced antiapoptotic Bcl-xL protein enhances cell survival and drug resistance. Free Radic Biol Med. 2013; 57:119-31. PMC: 3606082. DOI: 10.1016/j.freeradbiomed.2012.12.014. View

11.

Chen K, Mai Z, Zhou Y, Gao X, Yu B . Low NRF2 mRNA expression in spermatozoa from men with low sperm motility. Tohoku J Exp Med. 2012; 228(3):259-66. DOI: 10.1620/tjem.228.259. View

12.

JOHNSEN S . Testicular biopsy score count--a method for registration of spermatogenesis in human testes: normal values and results in 335 hypogonadal males. Hormones. 1970; 1(1):2-25. DOI: 10.1159/000178170. View

13.

Dodson M, Castro-Portuguez R, Zhang D . NRF2 plays a critical role in mitigating lipid peroxidation and ferroptosis. Redox Biol. 2019; 23:101107. PMC: 6859567. DOI: 10.1016/j.redox.2019.101107. View

14.

Li Z . Role of antioxidants in preventing testicular ischemia‑reperfusion injury: a narrative review. Eur Rev Med Pharmacol Sci. 2023; 26(24):9126-9143. DOI: 10.26355/eurrev_202212_30663. View

15.

Schlegel P . Human Spermatogenesis: Insights From the Clinical Care of Men With Infertility. Front Endocrinol (Lausanne). 2022; 13:889959. PMC: 9159388. DOI: 10.3389/fendo.2022.889959. View

16.

Mazaud-Guittot S, Meugnier E, Pesenti S, Wu X, Vidal H, Gow A . Claudin 11 deficiency in mice results in loss of the Sertoli cell epithelial phenotype in the testis. Biol Reprod. 2009; 82(1):202-13. PMC: 2802123. DOI: 10.1095/biolreprod.109.078907. View

17.

Wajda A, Lapczuk J, Grabowska M, Slojewski M, Laszczynska M, Urasinska E . Nuclear factor E2-related factor-2 (Nrf2) expression and regulation in male reproductive tract. Pharmacol Rep. 2016; 68(1):101-8. DOI: 10.1016/j.pharep.2015.07.005. View

18.

Sagare-Patil V, Modi D . Progesterone activates Janus Kinase 1/2 and activators of transcription 1 (JAK1-2/STAT1) pathway in human spermatozoa. Andrologia. 2012; 45(3):178-86. DOI: 10.1111/j.1439-0272.2012.01332.x. View

19.

Niture S, Jaiswal A . Nrf2 protein up-regulates antiapoptotic protein Bcl-2 and prevents cellular apoptosis. J Biol Chem. 2012; 287(13):9873-9886. PMC: 3323009. DOI: 10.1074/jbc.M111.312694. View

20.

Yamamoto M, Kensler T, Motohashi H . The KEAP1-NRF2 System: a Thiol-Based Sensor-Effector Apparatus for Maintaining Redox Homeostasis. Physiol Rev. 2018; 98(3):1169-1203. PMC: 9762786. DOI: 10.1152/physrev.00023.2017. View