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ADAM17 substrate release in proximal tubule drives kidney fibrosis

Eirini Kefaloyianni1, Muthu Lakshmi Muthu1, Jakob Kaeppler1

  • 1Renal Division, Brigham and Women's Hospital, Boston, Massachusetts, USA.

JCI Insight
|September 20, 2016
PubMed

Insights

Kidney fibrosis, a major health issue, is driven by the ADAM17 enzyme pathway. Inhibiting ADAM17 or its substrate amphiregulin (AREG) shows promise for treating kidney fibrosis.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Nephrology

Background:

  • Kidney fibrosis is a significant cause of morbidity and mortality globally.
  • The precise molecular mechanisms underlying kidney fibrosis remain incompletely understood.

Purpose of the Study:

  • To elucidate the molecular mechanisms driving kidney fibrosis.
  • To investigate the role of a disintegrin and metalloprotease 17 (ADAM17) and its substrates in kidney fibrosis.
  • To evaluate the therapeutic potential of targeting the ADAM17 pathway.

Main Methods:

  • Utilized ADAM17 hypomorphic mice, ADAM17 inhibitor-treated mice, and inducible ADAM17 knockout mice.
  • Conducted in vitro studies using proximal tubule cells.
  • Analyzed human urine and kidney biopsy samples from patients with acute kidney injury (AKI) and chronic kidney disease (CKD).

Main Results:

  • Sustained elevation of ADAM17, pro-tumor necrosis factor-alpha (pro-TNFα), and pro-amphiregulin (pro-AREG) were identified as key drivers of kidney injury-induced fibrosis.
  • Persistent activation of the epidermal growth factor receptor (EGFR) by these factors promotes profibrotic signaling.
  • Inhibition of ADAM17 or genetic ablation significantly protected against kidney fibrosis.
  • Elevated soluble AREG in human urine and correlated expression of ADAM17 and AREG with fibrosis markers in kidney biopsies were observed.

Conclusions:

  • The ADAM17 pathway, including its substrates AREG and TNFα, plays a critical role in the pathogenesis of kidney fibrosis.
  • Targeting ADAM17 offers a potential therapeutic strategy for treating kidney fibrosis in humans.

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