Cannabinoid Receptor 1 Blockade Ameliorates Albuminuria in Experimental Diabetic Nephropathy

Abstract

OBJECTIVECannabinoid receptor 1 (CB1) is localized in the central nervous system and in peripheral tissues involved in energy metabolism control. However, CB1 receptors are also expressed at low level within the glomeruli, and the aim of this study was to investigate their potential relevance in the pathogenesis of proteinuria in experimental type 1 diabetes.RESEARCH DESIGN AND METHODSStreptozotocin-induced diabetic mice were treated with N-(piperidin-1-yl)-5-(4-iodophenyl)-1-(2,3-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (AM251), a selective CB1-receptor antagonist, at the dosage of 1 mg · kg−1 · day−1 via intraperitoneal injection for 14 weeks. Urinary albumin excretion was measured by enzyme-linked immunosorbent assay. CB1 receptor expression was studied by immunohistochemistry, immunoblotting, and real-time PCR. Expression of nephrin, podocin, synaptopodin, and zonula occludens-1 (ZO-1) was assessed by immunofluorescence and real-time PCR. Fibronectin, transforming growth factor-β1 (TGF-β1), and connective tissue growth factor (CTGF) mRNA levels were quantitated by real-time PCR.RESULTSIn diabetic mice, the CB1 receptor was overexpressed within the glomeruli, predominantly by glomerular podocytes. Blockade of the CB1 receptor did not affect body weight, blood glucose, and blood pressure levels in either diabetic or control mice. Albuminuria was increased in diabetic mice compared with control animals and was significantly ameliorated by treatment with AM251. Furthermore, CB1 blockade completely prevented diabetes-induced downregulation of nephrin, podocin, and ZO-1. By contrast overexpression of fibronectin, TGF-β1, and CTGF in renal cortex of diabetic mice was unaltered by AM251 administration.CONCLUSIONSIn experimental type 1 diabetes, the CB1 receptor is overexpressed by glomerular podocytes, and blockade of the CB1 receptor ameliorates albuminuria possibly via prevention of nephrin, podocin, and ZO-1 loss.

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].…”

“…In the first model induced by streptozotocin (STZ), kidney expression of the CB 1 receptor is enhanced in both diabetic mice [33] and rats [37]. More specifically, colocalization of the CB 1 receptor with nephrin points to their predominant expression in podocytes.…”

“…More specifically, colocalization of the CB 1 receptor with nephrin points to their predominant expression in podocytes. Moreover, pharmacological inhibition of the CB 1 receptor by AM251 ameliorates STZ-induced albuminuria and prevents the downregulation of podocyte proteins implicated in the maintenance of glomerular permselectivity to proteins [33]. Because proteinuria is an independent predictor of renal outcome in patients with type 1 DM [64], a recent study tested the specific role of CB 1 receptors in mediating urinary protein excretion.…”