Proximal Tubular Cannabinoid-1 Receptor Regulates Obesity-Induced CKD

J Am Soc Nephrol. 2017 Dec;28(12):3518-3532. doi: 10.1681/ASN.2016101085. Epub 2017 Aug 31.

Abstract

Obesity-related structural and functional changes in the kidney develop early in the course of obesity and occur independently of hypertension, diabetes, and dyslipidemia. Activating the renal cannabinoid-1 receptor (CB1R) induces nephropathy, whereas CB1R blockade improves kidney function. Whether these effects are mediated via a specific cell type within the kidney remains unknown. Here, we show that specific deletion of CB1R in the renal proximal tubule cells did not protect the mice from obesity, but markedly attenuated the obesity-induced lipid accumulation in the kidney and renal dysfunction, injury, inflammation, and fibrosis. These effects associated with increased activation of liver kinase B1 and the energy sensor AMP-activated protein kinase, as well as enhanced fatty acid β-oxidation. Collectively, these findings indicate that renal proximal tubule cell CB1R contributes to the pathogenesis of obesity-induced renal lipotoxicity and nephropathy by regulating the liver kinase B1/AMP-activated protein kinase signaling pathway.

Keywords: AMPK; CB1 receptor; Endocannabinoids; Renal Proximal Tubular Cell; chronic kidney disease; obesity.

MeSH terms

  • Animals
  • Body Weight
  • Cell Line
  • Fatty Acids / metabolism
  • Fibrosis
  • Gene Deletion
  • Gene Expression Regulation*
  • Genotype
  • Heterozygote
  • Humans
  • Inflammation
  • Kidney Failure, Chronic / complications
  • Kidney Failure, Chronic / metabolism*
  • Kidney Tubules, Proximal / pathology*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Obesity / complications
  • Obesity / metabolism*
  • Oxygen / chemistry
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism
  • Receptor, Cannabinoid, CB1 / genetics
  • Receptor, Cannabinoid, CB1 / metabolism*
  • Signal Transduction

Substances

  • Fatty Acids
  • Receptor, Cannabinoid, CB1
  • Stk11 protein, mouse
  • Protein-Serine-Threonine Kinases
  • Oxygen