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Increased mTOR signaling secondary to a human ILK missense variant inhibits nephrogenesis with decreased metabolism

Xiangyue Hu1, Dana Kablawi1, Wout F J Feitz2

  • 1Program in Developmental and Stem Cell Biology, The Hospital for Sick Children, Toronto, ON, Canada; Institute of Medical Science, University of Toronto, Toronto, ON, Canada.

Mechanisms of Ageing and Development
|September 21, 2025
PubMed

Insights

Increased mTOR signaling, linked to a human CAKUT variant in Integrin-Linked Kinase (ILK), impairs kidney development by reducing nephron formation and cell maturation. Rapamycin partially rescued ureteric branching defects.

Area of Science:

  • Developmental Biology
  • Genetics
  • Nephrology

Background:

  • Nephrogenesis, the formation of new nephrons, is crucial for kidney function and is impaired in Congenital Anomalies of the Kidney and Urinary Tract (CAKUT).
  • Mechanisms governing nephron number during embryonic development remain largely unknown.
  • CAKUT is associated with adult-onset cardiovascular and renal diseases.

Purpose of the Study:

  • To investigate the role of mTOR signaling in murine nephrogenesis.
  • To elucidate the functional consequences of a human CAKUT-associated Integrin-Linked Kinase (ILK) variant (ILKT173I).

Main Methods:

  • Generated a mouse model with the human ILKT173I variant.
  • Utilized rapamycin to assess rescue effects.
  • Performed transcriptomic analysis and immunostaining on embryonic kidney cells.
  • Conducted morphologic analysis and metabolic profiling of nephrogenic cells.

Main Results:

  • The ILKT173I variant increased mTOR signaling in kidneys, leading to reduced nephron number and ureteric branching.
  • Rapamycin treatment rescued ureteric branching defects.
  • Elevated mTOR signaling was localized to non-ureteric mesenchyme.
  • ILKT173I impaired nephrogenic cell maturation, proliferation, and metabolism, with decreased oxidative ATP production.

Conclusions:

  • Excessive mTOR signaling, downstream of ILKT173I, detrimentally affects nephrogenesis by inhibiting nephrogenic cell maturation, proliferation, and metabolism.
  • This study identifies a novel mechanism linking ILK, mTOR signaling, and kidney development, with implications for CAKUT and related diseases.
Keywords:
Cell signalingDevelopmental biologyKidney developmentMetabolismPediatric nephrology

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