Blockade of Cannabinoid Receptor 1 Improves Insulin Resistance, Lipid Metabolism, and Diabetic Nephropathy in db/db Mice

Abstract

The endocannabinoid system is important in the pathogenesis of obesity-related metabolic disorders. However, the effect of inhibiting the endocannabinoid system in type 2 diabetic nephropathy is unclear. Therefore, we examined the effect of the cannabinoid (CB)1 receptor antagonist, SR141716, on insulin resistance and diabetic nephropathy in db/db mice. Six-week-old db/db mice were treated with the CB1-specific antagonist SR141716 (10 mg/kg · d) for 3 months. Treatment with SR141716 significantly improved insulin resistance and lipid abnormalities. Concomitantly, CB1 antagonism improved cardiac functional and morphological abnormality, hepatic steatosis, and phenotypic changes of adipocytes into small differentiated forms, associated with increased adiponectin expression and decreased lipid hydroperoxide levels. CB1 receptor was overexpressed in diabetic kidneys, especially in podocytes. Treatment with the SR141716 markedly decreased urinary albumin excretion and mesangial expansion and suppressed profibrotic and proinflammatory cytokine synthesis. Furthermore, SR141716 improved renal lipid metabolism and decreased urinary 8-isoprostane levels, renal lipid hydroperoxide content, and renal lipid content. In cultured podocytes, high-glucose stimulation increased CB1 receptor expression, and SR141716 treatment abolished high-glucose-induced up-regulation of collagen and plasminogen activator inhibitor-1 synthesis. Additionally, knockdown of CB1 receptor expression by stealth small interfering RNA abolished high-glucose-induced sterol-regulatory element-binding protein-1 expression in podocytes. These findings suggest that CB1 blockade improves insulin resistance and protect against renal injury through both metabolic and antifibrotic effects in type 2 diabetic nephropathy. Targeting CB1 blockade could therefore provide a new therapeutic target to prevent type 2 diabetic nephropathy.

CB1 receptor blockade counters age‐induced insulin resistance and metabolic dysfunction

“…Indeed, it is possible that the improvements in insulin sensitivity that are conveyed by rimonabant in aged mice may be due, at least in part, to reductions in adiposity. However, it should be noted that previous studies utilizing hyperinsulinaemic‐euglycaemic clamps and/or ITT (insulin tolerance test), have documented the ability of rimonabant to improve insulin sensitivity without promoting significant reductions in body fat mass or visceral fat in db/db mice and diet‐induced obese dogs, respectively (Kim et al ., 2012; Nam et al ., 2012). Together with our previous work reporting direct insulin‐sensitizing actions by rimonabant in rat skeletal L6 myotubes (Lipina et al ., 2010), these findings indicate that CB1R inhibition may at least partly enhance insulin sensitivity in aged mice independently of its ability to normalize age‐related adiposity.…”

Synthetic Cannabinoids and Acute Kidney Injury

“…It was shown that XLR-11 and UR-144 had Δ9-THS-like activity in animals and bind to the brain cannabinoid receptor (CB1 receptor) in in vitro studies. CB1 receptors are also expressed in kidney cells, including podocytes and proximal tubule cells (10)(11)(12), and we suggest that the AKI related to SCB might be related to CB1 receptors in the kidneys. Th ere are limited data on the CB1 receptor and kidney function.…”

“…Th ere are limited data on the CB1 receptor and kidney function. However, blockade of CB1 receptors has been shown to have protective eff ects on renal function and ameliorate albuminuria in certain groups of mice (10,11,13).…”

The emerging role of the endocannabinoid system in the pathogenesis and treatment of kidney diseases

“…Several recent reports (Table 1) have documented the presence of functional CB 1 receptor in the entire kidney [15,[33][34][35][36][37][38][40][41][42], including different parts of the nephron such as afferent and efferent arterioles [39], glomeruli [33,38,40,42,43], tubules [15], the loop of Henle [44], and collecting ducts [15]. It is also expressed in various subtypes of kidney cells such as podocytes [33,41,43,45,46], proximal and distal tubular epithelial cells [15,34,37,38,40,41,[47][48][49], and mesangial cells [50,54]. Moreover, CB 1 receptors are expressed in human clear-and chromophobe-renal cell carcinomas, as well as in renal oncocytoma [55,56].…”

“…To date, two murine models for type 2 DM have been utilized to test the involvement of CB 1 receptor in DN. Using the diabetic db/db mouse model, Nam et al [43] documented preferentially increased CB 1 receptor expression in glomerular podocytes and demonstrated that SR141716 treatment significantly inhibits the expression of profibrotic and proinflammatory molecules in the diabetic kidney. Insights into the mechanism by which the CB 1 receptor modulates podocyte injury in type 2 DM were found in a recent report by Jourdan et al [41], who used the well-established Zucker diabetic fatty (ZDF) rat model.…”