title: 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 (CB1R) 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 renin-angiotensin system (RAS), oxidative/nitrative stress, podocyte loss, and increased CB1R expression in glomeruli. Peripheral CB1R 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 CB1R expression, without affecting the marked hyperglycemia. In cultured human podocytes, CB1R and desmin gene expression were increased and podocin and nephrin content were decreased by either the CB1R agonist arachydonoyl-2'-chloroethylamide, angiotensin II, or high glucose, and the effects of all three were antagonized by CB1R blockade or siRNA-mediated knockdown of CNR1 (the cannabinoid type 1 receptor gene). We conclude that increased CB1R 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 CB1R blockade.
authors.affiliation: Laboratory of Physiologic Studies, Section on Neuroendocrinology, and jourdant@mail.nih.gov george.kunos@nih.gov.
authors.forename: Tony
authors.initials: T
authors.lastname: Jourdan
authors.affiliation: Laboratory of Physiologic Studies, Section on Neuroendocrinology, and.
authors.forename: Gergő
authors.initials: G
authors.lastname: Szanda
authors.affiliation: Kidney Diseases Section, National Institute on Diabetes, Digestive, and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892; The Johns Hopkins University School of Medicine, Baltimore, MD 21205; and.
authors.forename: Avi Z
authors.initials: AZ
authors.lastname: Rosenberg
authors.affiliation: Laboratory of Physiologic Studies, Section on Neuroendocrinology, and.
authors.forename: Joseph
authors.initials: J
authors.lastname: Tam
authors.affiliation: Laboratory of Physiologic Studies, Section on Neuroendocrinology, and.
authors.forename: Brian James
authors.initials: BJ
authors.lastname: Earley
authors.affiliation: Laboratory of Physiologic Studies, Section on Neuroendocrinology, and.
authors.forename: Grzegorz
authors.initials: G
authors.lastname: Godlewski
authors.affiliation: Laboratory of Physiologic Studies, Section on Neuroendocrinology, and.
authors.forename: Resat
authors.initials: R
authors.lastname: Cinar
authors.affiliation: Laboratory of Physiologic Studies, Section on Neuroendocrinology, and.
authors.forename: Ziyi
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Laboratory of Physiologic Studies, Section on Neuroendocrinology, and.
authors.forename: Jie
authors.initials: J
authors.lastname: Liu
authors.affiliation: Skaggs School of Pharmacy and Pharmaceutical Sciences, Department of Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO 80045.
authors.forename: Cynthia
authors.initials: C
authors.lastname: Ju
authors.affiliation: Section on Oxidative Stress and Tissue Injury, Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism.
authors.forename: Pál
authors.initials: P
authors.lastname: Pacher
authors.affiliation: Laboratory of Physiologic Studies, Section on Neuroendocrinology, and jourdant@mail.nih.gov george.kunos@nih.gov.
authors.forename: George
authors.initials: G
authors.lastname: Kunos
mesh_terms: D000704:Analysis of Variance; D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D001095:Arachidonic Acids / Q000494:pharmacology; D003893:Desmin / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000150:complications*; D003928:Diabetic Nephropathies / Q000209:etiology / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D019808:Losartan / Q000494:pharmacology; D008954:Models, Biological; D050199:Podocytes / Q000378:metabolism*; D011720:Pyrazoles / Q000138:chemical synthesis / Q000494:pharmacology; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics / Q000494:pharmacology; D051381:Rats; D011924:Rats, Zucker; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013449:Sulfonamides / Q000138:chemical synthesis / Q000494:pharmacology
chemical_list: C544067:Agtr1a protein, rat; D001095:Arachidonic Acids; D003893:Desmin; D011720:Pyrazoles; D034741:RNA, Small Interfering; D044140:Receptor, Angiotensin, Type 1; D043884:Receptor, Cannabinoid, CB1; D013449:Sulfonamides; C119325:arachidonyl-2-chloroethylamide; D000804:Angiotensin II; C577200:JD5037; D019808:Losartan
keywords: angiotensin II; endocannabinoid; hyperglycemia; nephropathy; podocyte