TY - JOUR
T1 - Overactive cannabinoid 1 receptor in podocytes drives type 2 diabetic nephropathy
AU - Jourdan, Tony
AU - Szandaa, Gergo
AU - Rosenberg, Avi Z.
AU - Tam, Joseph
AU - Earley, Brian James
AU - Godlewski, Grzegorz
AU - Cinar, Resat
AU - Liu, Ziyi
AU - Liu, Jie
AU - Ju, Cynthia
AU - Pacher, Pál
AU - Kunos, George
N1 - Publisher Copyright:
© 2014, National Academy of Sciences. All rights reserved.
PY - 2014/12/16
Y1 - 2014/12/16
N2 - 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 reninangiotensin 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.
AB - 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 reninangiotensin 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.
KW - Angiotensin II
KW - Endocannabinoid
KW - Hyperglycemia
KW - Nephropathy
KW - Podocyte
UR - http://www.scopus.com/inward/record.url?scp=84918571992&partnerID=8YFLogxK
U2 - 10.1073/pnas.1419901111
DO - 10.1073/pnas.1419901111
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C2 - 25422468
AN - SCOPUS:84918571992
SN - 0027-8424
VL - 111
SP - E5420-E5428
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 50
ER -
