Kidney growth and hypertrophy: the role of mTOR and vesicle trafficking

Area of Science:

• Cellular biology
• Organ physiology
• Molecular signaling

Background:

• Organs, including the kidney, exhibit proportional growth.
• Compensatory hypertrophy occurs when one kidney is removed, with the remaining organ enlarging.
• The mechanistic target of rapamycin complex 1 (mTORC1) pathway is crucial for cellular growth and proliferation.

Purpose of the Study:

• To elucidate the molecular mechanisms underlying kidney growth during maturation.
• To investigate the signaling pathways involved in compensatory kidney hypertrophy after unilateral nephrectomy.
• To differentiate the pathways regulating normal growth from those mediating adaptive growth.

Main Methods:

• Utilized a comprehensive series of studies to investigate kidney growth.
• Examined the role of the mTORC1 signaling pathway and its components.
• Investigated the involvement of growth factors, amino acids, and specific kinases (PI3K, PDK, AKT, mTORC2, VPS34).

Main Results:

• Kidney maturation involves mTORC1 signaling, induced by EGF-like peptides and requiring PI3K, PDK, AKT, and mTORC2.
• Activation of mTORC1 during maturation involves TSC and RHEB within a lysosome-localized complex.
• Compensatory kidney growth is mediated by amino acids acting on mTORC1 independently of the maturation pathway.
• Compensatory growth requires class III PI3K (VPS34), known for its role in lysosomal vesicle trafficking.

Conclusions:

• Kidney growth during maturation and compensatory hypertrophy are regulated by distinct molecular signaling pathways.
• mTORC1 is a central regulator, but its activation mechanisms differ based on the growth context (maturation vs. compensation).
• Amino acid sensing via VPS34-dependent mTORC1 activation is critical for compensatory kidney hypertrophy.