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JAK Inhibition Prevents DNA Damage and Apoptosis in Testicular Ischemia-Reperfusion Injury via Modulation of the

Farah Khashab1, Farah Al-Saleh1, Nora Al-Kandari1

  • 1Department of Biochemistry, Faculty of Medicine, Kuwait University, Safat 13110, Kuwait.

International Journal of Molecular Sciences
|December 24, 2021
PubMed

Insights

Testicular ischemia reperfusion injury (tIRI) causes germ cell apoptosis via oxidative DNA damage. JAK2 activation directly links to DNA damage response pathways, leading to cell death, a process inhibited by AG490.

Area of Science:

  • Reproductive biology
  • Molecular toxicology
  • Cellular signaling

Background:

  • Testicular ischemia reperfusion injury (tIRI) induces oxidative stress, DNA damage, and germ cell apoptosis (GCA).
  • The precise molecular mechanisms linking JAK2 activation to DNA damage response (DDR) and GCA in tIRI remain unclear.

Purpose of the Study:

  • To investigate the direct role of Janus Kinase 2 (JAK2) activation in tIRI-induced GCA.
  • To elucidate the connection between JAK2 signaling, oxidative DNA damage, and DDR pathways in tIRI.

Main Methods:

  • Male Sprague Dawley rats underwent sham operation, unilateral tIRI, or tIRI with JAK2 inhibitor AG490.
  • Immunohistochemistry, colorimetric assays, TUNEL staining, and Western blot were used to assess JAK2/STAT pathway activation, DNA damage markers (DSB, AP sites, 8OHdG), apoptosis markers (caspase 9, 3, PARP), and DDR pathways (ATM/Chk2/H2AX, ATR/Chk1).

Main Results:

  • tIRI significantly increased JAK2/STAT1/STAT3 phosphorylation, DNA damage, and apoptosis markers.
  • Activation of ATM/Chk2/H2AX and ATR/Chk1 DDR pathways was observed following tIRI.
  • AG490 treatment effectively prevented tIRI-induced spermatogenic arrest, DNA damage, apoptosis, and DDR pathway activation by inhibiting JAK2.

Conclusions:

  • JAK2 plays a critical role in regulating tIRI-induced GCA and associated oxidative DNA damage.
  • JAK2 activation triggers the ATM/Chk2/H2AX and ATR/Chk1 DDR pathways, ultimately leading to germ cell apoptosis.
  • Despite DDR activation, the cell initiates apoptosis in response to tIRI, highlighting JAK2's central regulatory function.
Keywords:
ATMATRDNA damage responseJAK/STATapoptosisischemia-reperfusion injuryoxidative stress

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