Proximal Tubular Cannabinoid-1 Receptor Regulates Obesity-Induced CKD

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 (CBR) induces nephropathy, whereas CBR blockade improves kidney function. Whether these effects are mediated a specific cell type within the kidney remains unknown. Here, we show that specific deletion of CBR 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 -oxidation. Collectively, these findings indicate that renal proximal tubule cell CBR contributes to the pathogenesis of obesity-induced renal lipotoxicity and nephropathy by regulating the liver kinase B1/AMP-activated protein kinase signaling pathway.

Cannabinoid‐1 receptor regulates mitochondrial dynamics and function in renal proximal tubular cells

“…Mice were metabolically assessed using the Promethion High‐Definition Behavioral Phenotyping System (Sable Instruments, Inc., Las Vegas, Nevada) as described previously …”

“…eCBs were extracted, purified and quantified in kidney and cells, as described previously . LC–MS/MS was analysed on an AB Sciex (Framingham, Massachusetts) Triple Quad 5500 mass spectrometer coupled with a Shimadzu (Kyoto, Japan) UHPLC System.…”

“…The eCB/CB 1 R system is highly overactive during obesity, and both central and peripheral stimulations of this system have been suggested to mediate obesity‐related comorbidities, contributing to the development of the metabolic syndrome . Recently, we have demonstrated that over‐activated CB 1 R mediates obesity‐induced kidney injury, dysfunction, inflammation and fibrosis by compromising the function of renal proximal tubular cells (RPTCs) . RPTCs are metabolically active and reabsorb up to 80% of the solute and water passing through the nephron via specialized ATP‐dependent membrane transporters .…”

In Vivo Anticancer Activity of a Nontoxic Inert Phenolato Titanium Complex: High Efficacy on Solid Tumors Alone and Combined with Platinum Drugs

“…Histological examination for tubular damage : Following euthanasia, kidneys were removed and fixed with 10 % formalin, renal tissues were sectioned (3 μm) and stained with periodic acid–Schiff (PAS) reagents for histological examination. Tubular damage in PAS‐stained sections was examined by microscopy (200× magnification) as described earlier …”

Cannabinoid‐1 receptor deletion in podocytes mitigates both glomerular and tubular dysfunction in a mouse model of diabetic nephropathy

“…In addition to its well‐documented role in obesity and its metabolic complications, the ECS has been implicated in the pathogenesis of CKD, including DN . Both CB 1 R and CB 2 R are expressed in the human and rodent kidney, particularly in mesangial cells, podocytes and proximal tubular cells . Enzymes responsible for the biosynthesis and degradation of endocannabinoids are also expressed in the kidney .…”