Endocannabinoid System and the Kidneys: From Renal Physiology to Injury and Disease

Abstract

Introduction: As the prevalence of kidney disease continues to rise worldwide, there is accumulating evidence that kidney injury and dysfunction, whether acute or chronic, is associated with major adverse outcomes, including mortality. Meanwhile, effective therapeutic options in the treatment of acute kidney injury (AKI) and chronic kidney disease (CKD) have been sparse. Many of the effective treatments that are routinely utilized for different pathologies in patients without kidney disease have failed to demonstrate efficacy in those with renal dysfunction. Hence, there is an urgent need for discovery of novel pathways that can be targeted for innovative and effective clinical therapies in renal disease states. Discussion: There is now accumulating evidence that the endocannabinoid (EC) system plays a prominent role in normal renal homeostasis and function. In addition, numerous recent studies have described mechanisms through which alteration in the EC system can contribute to kidney damage and disease. These include a potential role for cannabinoid receptors in tubulo-glomerular damage and fibrosis, which are common features of AKI, interstitial nephritis, glomerulopathy, and other conditions leading to AKI and CKD. Conclusion: These findings suggest that manipulating the EC system may be an effective therapeutic strategy for the treatment of kidney disease and injury. However, further mechanistic studies are needed to fully delineate the role of this system in various conditions affecting the kidneys. Furthermore, while most of the current literature is focused on the role of the EC system as a whole in renal pathophysiology, future studies will also need to clarify the contribution of each component of this system, including the EC mediators, in the pathogenesis of kidney disease and their potential role as part of a therapeutic strategy.

Effect of Added Dietary Betaine and Soluble Fiber on Metabolites and Fecal Microbiome in Dogs with Early Renal Disease

“…N-methylproline, a fibrosis biomarker [ 36 ], was also significantly decreased after consumption of the test foods. The levels of several endocannabinoids increased with the test foods, which are of interest since the endocannabinoid system is important in normal renal function [ 37 ].…”

Interference with TGFβ1-Mediated Inflammation and Fibrosis Underlies Reno-Protective Effects of the CB1 Receptor Neutral Antagonists AM6545 and AM4113 in a Rat Model of Metabolic Syndrome

“…It has been established that a full system of endocannabinoids exists in the kidney and has a significant role in renal homeostasis as well as in the development of diabetic nephropathy and conditions such as CKD [ 18 ]. CB1 and CB2 receptors were reported to be present in the various parts of the nephron as well as other renal cells in both humans and rodents [ 19 ]. Furthermore, the endocannabinoid system in the kidney plays a predominant role in renal hemodynamics [ 20 ].…”

Modulation of Endocannabinoids by Caloric Restriction Is Conserved in Mice but Is Not Required for Protection from Acute Kidney Injury

“…NAEs comprise a heterogeneous group of lipid-derived molecules that can activate the G-protein-coupled receptors CB-1 and CB-2 in the central nervous system and peripheral organs (e.g., the kidney) [ 32 ]. NAE signaling is involved in the regulation of food intake [ 33 ], energy metabolism [ 34 ], inflammation [ 35 ], and vascular tonus [ 28 ]. Nevertheless, the exact underlying mechanisms remain elusive [ 28 ].…”

“…Consequently, the hypothesis that the reduction of NAEs upon CR may also be involved in organ protection in mammals is an important research question. NAEs are endocannabinoids and as such lipid-derived signaling molecules that are, among other organs-synthesized in the kidney [ 28 , 29 , 30 ]. They are formed within the tissues by N-acyl-ethanolamine phospholipids (NAPE) catalyzed by a membrane-associated NAPE-hydrolyzing phospholipase D (NAPE-PLD) [ 31 ].…”