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Proximal Tubular Cannabinoid-1 Receptor Regulates Obesity-Induced CKD

Shiran Udi1, Liad Hinden1, Brian Earley2

  • 1Obesity and Metabolism Laboratory, Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel.

Journal of the American Society of Nephrology : JASN
|September 2, 2017
PubMed

Insights

Obesity causes kidney damage early on. Blocking cannabinoid-1 receptors (CB1R) in kidney tubule cells reduces obesity-related kidney fat, dysfunction, and injury by activating key energy pathways.

Area of Science:

  • Nephrology
  • Metabolic Diseases
  • Molecular Biology

Background:

  • Obesity leads to early kidney structural and functional changes, independent of other conditions.
  • Activating renal cannabinoid-1 receptor (CB1R) causes kidney damage, while blocking it improves kidney function.
  • The specific kidney cell type mediating these CB1R effects is not fully understood.

Purpose of the Study:

  • To investigate the role of CB1R in renal proximal tubule cells in obesity-induced kidney disease.
  • To determine if deleting CB1R in these cells mitigates kidney pathology.
  • To elucidate the molecular mechanisms, including energy metabolism pathways, involved.

Main Methods:

  • Generation of mice with specific CB1R deletion in renal proximal tubule cells.
  • Induction of obesity and assessment of kidney structure, function, and lipid accumulation.
  • Analysis of signaling pathways, including liver kinase B1 (LKB1) and AMP-activated protein kinase (AMPK), and fatty acid oxidation.

Main Results:

  • Specific deletion of CB1R in renal proximal tubule cells did not prevent obesity but significantly reduced kidney lipid accumulation.
  • This deletion attenuated obesity-induced renal dysfunction, injury, inflammation, and fibrosis.
  • The protective effects were linked to increased LKB1/AMPK activation and enhanced fatty acid beta-oxidation.

Conclusions:

  • Renal proximal tubule cell CB1R plays a critical role in obesity-induced kidney lipotoxicity and nephropathy.
  • Targeting CB1R in these specific kidney cells may offer a therapeutic strategy.
  • The LKB1/AMPK signaling pathway is a key mediator of these effects.
Keywords:
AMPKCB1 receptorEndocannabinoidsRenal Proximal Tubular Cellchronic kidney diseaseobesity

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