Hebrew University campus .
(photo credit: Wikimedia Commons)
A new Hebrew University of Jerusalem study has provided insights into the mechanisms behind development of kidney damage due to obesity. The findings, which appear in an upcoming issue of the Journal of the American Society of Nephrology, point to a potential target for protecting the kidney health of obese individuals.
Obesity-related kidney dysfunction develops early in the course of weight gain, justifying the search for novel regulators that could be targeted for therapy. Obesity can cause structural and functional changes in the kidneys, which may help explain why individuals with obesity face much higher risk of chronic kidney disease and kidney failure than that faced by non-diabetics. Although multiple metabolic factors have been proposed to contribute to obesity-induced kidney problems, the underlying mechanisms have not been completely understood.
To investigate, a team led by Dr. Joseph (Yossi) Tam and doctoral student Shiran Udi at Hebrew University’s Institute for Drug Research, examined the kidney cells responsible for the reabsorption of nutrients, while allowing other substances of no nutritional value to be excreted in the urine. These kidney cells, called renal proximal tubular cells (RPTCs), are especially sensitive to the accumulation of facts, or lipids, an effect called lipotoxicity.
The researchers examined the potential role of endocannabinoids – lipid molecules that interact with the cannabinoid-1 receptor (CB1R) and are abundantly expressed in the brain and periphery, including in the kidneys. Endocannabinoids are similar to the body’s own THC, the psychoactive component of marjuana, or cannabis. The discovery of cannabinoids in plants was made before the biological compound. Endocannabinoids act on the CB1R receptor in RPTC renal cell lipotoxicity. Mice that lacked expression of the receptor in the RPTC renal cells experienced significantly less obesity-induced lipid accumulation in the kidney and less kidney dysfunction, injury, inflammation and scarring.
Moreover, the study revealed the molecular signaling pathway involved in mediating the kidney injury and lipotoxicity in RPTC renal cells induced by the CB1R cellular receptors. Specifically, these harmful effects are associated with decreased activation of liver kinase B1 and the energy sensor AMP-activated protein kinase, as well as reduced fatty acid beta-oxidation.
The research shows that manipulating the cannabinoid-1 receptor specifically in the RPTC renal cells can provide a novel therapeutic intervention for treating obesity-induced nephropathy.
“This work provides a novel approach to slow the development of renal injury through chronic blockade of peripheral CB1Rs,” said Tam. “It also supports strategies aimed at reducing the activity of the endocannabinoid system, specifically in the kidney, to attenuate the development of RPTC dysfunction in obesity.”