Overactive cannabinoid 1 receptor in podocytes drives type 2 diabetic nephropathy

Abstract

Diabetic nephropathy is a major cause of end-stage kidney disease, and overactivity of the endocannabinoid/cannabinoid 1 receptor (CB 1 R) system contributes to diabetes and its complications. Zucker diabetic fatty (ZDF) rats develop type 2 diabetic nephropathy with albuminuria, reduced glomerular filtration, activation of the reninangiotensin system (RAS), oxidative/nitrative stress, podocyte loss, and increased CB 1 R expression in glomeruli. Peripheral CB 1 R blockade initiated in the prediabetic stage prevented these changes or reversed them when animals with fully developed diabetic nephropathy were treated. Treatment of diabetic ZDF rats with losartan, an angiotensin II receptor-1 (Agtr1) antagonist, attenuated the development of nephropathy and down-regulated renal cortical CB 1 R expression, without affecting the marked hyperglycemia. In cultured human podocytes, CB 1 R and desmin gene expression were increased and podocin and nephrin content were decreased by either the CB 1 R agonist arachydonoyl-2′-chloroethylamide, angiotensin II, or high glucose, and the effects of all three were antagonized by CB 1 R blockade or siRNA-mediated knockdown of CNR1 (the cannabinoid type 1 receptor gene). We conclude that increased CB 1 R signaling in podocytes contributes to the development of diabetic nephropathy and represents a common pathway through which both hyperglycemia and increased RAS activity exert their deleterious effects, highlighting the therapeutic potential of peripheral CB 1 R blockade.iabetic nephropathy, a highly prevalent and serious complication of both type 1 and type 2 diabetes mellitus and a leading cause of renal failure, is characterized by albuminuria, decreased glomerular filtration rate (GFR), mesangial expansion, thickening of the glomerular basement membrane, and glomerular sclerosis (1). Multiple mechanisms have been implicated in the development of diabetic nephropathy, including activation of the renin-angiotensin system (RAS) (2), increase in oxidative (3) and nitrosative/nitrative stress (4), as well as an increase in local inflammation (5).The endocannabinoid system plays a well-documented role in obesity and its metabolic complications, including insulin resistance and type 2 diabetes (T2DM). Globally acting cannabinoid 1 receptor (CB 1 R) antagonists/inverse agonists improve obesity-related insulin resistance, dyslipidemia, fatty liver, and β-cell loss, and attenuate obesity-related inflammatory changes both in preclinical models of diet-induced or genetic obesity and in clinical trials in overweight subjects with metabolic syndrome (reviewed in refs. 6 and 7). Global CB 1 R blockade also has beneficial effects in mouse models of type 1 and type 2 diabetic nephropathy (8-11). However, the therapeutic development of this class of compounds has been halted because of adverse neuropsychiatric side effects in a small proportion of treated subjects (12). Recent studies in rodent models have demonstrated that peripherally restricted CB 1 R antagonists are as effective as globally acti...

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

“…Several lines of evidence show that HG stimulation of podocytes significantly increases CB 1 receptor expression [41,43,45]. This elevation is associated with increased expression of collagen type IV, plasminogen activator inhibitor-1, and sterol regulatory element-binding transcription factor-1, and all of these effects are completely blocked by SR141716 and siRNA for the CB 1 receptor [43].…”

“…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].…”

“…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. Chronic (3 months) in vivo treatment of ZDF rats with the novel peripherally restricted CB 1 receptor antagonist, JD5037 [48], completely prevents renal pathologies related to glomerular dysfunction, which are strongly correlated with the specific expression of CB 1 receptors in podocytes and the expression of renal oxidative/nitrative stress markers [41].…”

“…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. Chronic (3 months) in vivo treatment of ZDF rats with the novel peripherally restricted CB 1 receptor antagonist, JD5037 [48], completely prevents renal pathologies related to glomerular dysfunction, which are strongly correlated with the specific expression of CB 1 receptors in podocytes and the expression of renal oxidative/nitrative stress markers [41]. These findings highlight the therapeutic potential of such peripheral compounds in DN, especially since the development and clinical testing of globally acting CB 1 receptor antagonists such as SR141716 has been halted due to neuropsychiatric side effects [67].…”

“…The relationship between the effect of HG and CB 1 receptor stimulation in podocytes has been tested by exposing cells to either 30 mM glucose or 5 μM arachidonyl-2′-chloroethylamide (a CB 1 receptor agonist). Both stimuli increase CB 1 receptor expression and decrease podocin and nephrin expressions, effects that are prevented by JD5037 and siRNA-mediated knockdown of podocyte CB 1 receptor [41]. Likewise, downregulation of podocyte CB 1 receptor expression or pharmacological blockade by AM251 prevents HG-induced Akt phosphorylation, endoplasmic reticulum (ER) stress-related protein expression, and phosphorylation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) [45].…”