Cannabinoid Receptor 1 Blockade Ameliorates Albuminuria in Experimental Diabetic Nephropathy

  1. Gabriella Gruden1
  1. 1Diabetic Nephropathy Laboratory, Department of Internal Medicine, University of Turin, Turin, Italy;
  2. 2Renal Research Laboratory, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Ospedale Maggiore Policlinico and Fondazione D'Amico per la Ricerca sulle Malattie Renali, Milan, Italy;
  3. 3MIA Consortium for Image Analysis, Milano Bicocca University, Milan, Italy;
  4. 4Endocannabinoid Research Group, Institute of Biomolecular Chemistry, Pozzuoli, Italy.
  1. Corresponding author: Gabriella Gruden, gabriella.gruden{at}unito.it.

Abstract

OBJECTIVE Cannabinoid 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 METHODS Streptozotocin-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.

RESULTS In 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, TGF1, and CTGF in renal cortex of diabetic mice was unaltered by AM251 administration.

CONCLUSIONS In 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.

Footnotes

  • The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

    • Received September 10, 2009.
    • Accepted December 30, 2009.

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  1. Diabetes vol. 59 no. 4 1046-1054
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