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TAK1 deficiency attenuates cisplatin-induced acute kidney injury

Jun Zhou1,2, Changlong An1,3, Xiaogao Jin1,4

  • 1Section of Nephrology, Department of Medicine, Baylor College of Medicine, Houston, Texas.

American Journal of Physiology. Renal Physiology
|December 10, 2019
PubMed

Insights

Transforming growth factor-β-activated kinase-1 (TAK1) plays a key role in cisplatin-induced acute kidney injury (AKI). Inhibiting TAK1 may offer a new treatment strategy for kidney damage caused by cisplatin.

Area of Science:

  • Nephrology
  • Molecular Biology
  • Oncology

Background:

  • Cisplatin chemotherapy is widely used but can cause acute kidney injury (AKI).
  • The precise molecular pathways driving cisplatin-induced AKI remain incompletely understood.
  • Transforming growth factor-β-activated kinase-1 (TAK1) is implicated in cellular stress responses.

Purpose of the Study:

  • To investigate the role of TAK1 in the development of cisplatin-induced AKI.
  • To determine if TAK1 deficiency in proximal tubule cells mitigates kidney damage from cisplatin.
  • To elucidate the signaling pathways activated by cisplatin involving TAK1.

Main Methods:

  • Comparison of cisplatin-treated wild-type mice and mice with proximal tubule-specific TAK1 deficiency.
  • Assessment of kidney function, tubular injury, and apoptosis markers.
  • Analysis of caspase-3 activation, inflammatory molecule expression, and JNK phosphorylation.

Main Results:

  • Proximal tubule TAK1-deficient mice exhibited significantly reduced kidney dysfunction, tubular damage, and apoptosis following cisplatin administration compared to wild-type controls.
  • Conditional disruption of TAK1 in proximal tubular epithelial cells led to decreased caspase-3 activation, reduced expression of proinflammatory molecules, and lower JNK phosphorylation.
  • Cisplatin treatment activated the TAK1-JNK signaling pathway, contributing to tubular cell apoptosis and inflammation.

Conclusions:

  • Cisplatin-induced AKI involves the activation of the TAK1-JNK signaling pathway.
  • TAK1 in proximal tubular epithelial cells is a critical mediator of cisplatin-induced kidney damage.
  • Targeting TAK1 presents a potential therapeutic avenue for preventing or treating cisplatin-induced nephrotoxicity.
Keywords:
acute kidney injuryapoptosisc-Jun NH2-terminal kinasechemokinescytokinestransforming growth factor-β-activated kinase-1

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