title: Exogenous kallikrein protects against diabetic nephropathy.
abstract: The kallikrein-kinin system has been shown to be involved in the development of diabetic nephropathy, but specific mechanisms are not fully understood. Here, we determined the renal-protective role of exogenous pancreatic kallikrein in diabetic mice and studied potential mechanisms in db/db type 2 diabetic and streptozotocin-induced type 1 diabetic mice. After the onset of diabetes, mice were treated with either pancreatic kallikrein (db/db+kallikrein, streptozotocin+kallikrein) or saline (db/db+saline, streptozotocin+saline) for 16 weeks, while another group of streptozotocin-induced diabetic mice received the same treatment after onset of albuminuria (streptozotocin'+kallikrein, streptozotocin'+saline). Db/m littermates or wild type mice were used as non-diabetic controls. Pancreatic kallikrein had no effects on body weight, blood glucose and blood pressure, but significantly reduced albuminuria among all three groups. Pathological analysis showed that exogenous kallikrein decreased the thickness of the glomerular basement membrane, protected against the effacement of foot process, the loss of endothelial fenestrae, and prevented the loss of podocytes in diabetic mice. Renal fibrosis, inflammation and oxidative stress were reduced in kallikrein-treated mice compared to diabetic controls. The expression of kininogen1, tissue kallikrein, kinin B1 and B2 receptors were all increased in the kallikrein-treated compared to saline-treated mice. Thus, exogenous pancreatic kallikrein both prevented and ameliorated diabetic nephropathy, which may be mediated by activating the kallikrein-kinin system.
authors.affiliation: Division of Endocrinology and Metabolism, Huashan Hospital, Fudan University, Shanghai, China.
authors.forename: Wenjuan
authors.initials: W
authors.lastname: Liu
authors.affiliation: Division of Endocrinology and Metabolism, Huashan Hospital, Fudan University, Shanghai, China.
authors.forename: Yeping
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Division of Endocrinology and Metabolism, Huashan Hospital, Fudan University, Shanghai, China; Department of Endocrinology, The Second People's Hospital, Wuhu, Anhui, China.
authors.forename: Yemei
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Endocrinology, High-tech District People's Hospital, Suzhou, Jiangsu, China.
authors.forename: Xiaolan
authors.initials: X
authors.lastname: Lu
authors.affiliation: Division of Endocrinology and Metabolism, Huashan Hospital, Fudan University, Shanghai, China.
authors.forename: Shizhe
authors.initials: S
authors.lastname: Guo
authors.affiliation: Department of Endocrinology, The Second Affiliated Hospital, Soochow University, Suzhou, Jiangsu, China.
authors.forename: Meng
authors.initials: M
authors.lastname: Wu
authors.affiliation: Department of Endocrinology, The Second Affiliated Hospital, Soochow University, Suzhou, Jiangsu, China.
authors.forename: Meng
authors.initials: M
authors.lastname: Wang
authors.affiliation: Department of Endocrinology, The First People's Hospital of Taichang, Jiangsu, China.
authors.forename: Linling
authors.initials: L
authors.lastname: Yan
authors.affiliation: Division of Endocrinology and Metabolism, Huashan Hospital, Fudan University, Shanghai, China; Institute of Endocrinology and Diabetology, Fudan University, Shanghai, China; Division of Endocrinology and Metabolism, Keenan Research Centre at the Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Ontario, Canada; Department of Physiology, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Qinghua
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Division of Endocrinology and Metabolism, Huashan Hospital, Fudan University, Shanghai, China.
authors.forename: Xiaolong
authors.initials: X
authors.lastname: Zhao
authors.affiliation: Jiangsu (Qianhong) Engineering Research Center for Innovative Biological Drugs, Changzhou, Jiangsu, China.
authors.forename: Xian
authors.initials: X
authors.lastname: Tong
authors.affiliation: Department of Endocrinology, The Second Affiliated Hospital, Soochow University, Suzhou, Jiangsu, China.
authors.forename: Ji
authors.initials: J
authors.lastname: Hu
authors.affiliation: Division of Endocrinology and Metabolism, Huashan Hospital, Fudan University, Shanghai, China; Institute of Endocrinology and Diabetology, Fudan University, Shanghai, China.
authors.forename: Yiming
authors.initials: Y
authors.lastname: Li
authors.affiliation: Division of Endocrinology and Metabolism, Huashan Hospital, Fudan University, Shanghai, China; Institute of Endocrinology and Diabetology, Fudan University, Shanghai, China.
authors.forename: Renming
authors.initials: R
authors.lastname: Hu
authors.affiliation: Renal Division, Joslin Diabetes Center, Boston, Massachusetts, USA.
authors.forename: Robert C
authors.initials: RC
authors.lastname: Stanton
authors.affiliation: Division of Endocrinology and Metabolism, Huashan Hospital, Fudan University, Shanghai, China; Institute of Endocrinology and Diabetology, Fudan University, Shanghai, China. Electronic address: zhaoyunzhang@fudan.edu.cn.
authors.forename: Zhaoyun
authors.initials: Z
authors.lastname: Zhang
mesh_terms: D000419:Albuminuria / Q000188:drug therapy* / Q000209:etiology; D000818:Animals; D003029:Coagulants / Q000494:pharmacology / Q000627:therapeutic use*; D003404:Creatinine / Q000097:blood; D003928:Diabetic Nephropathies / Q000150:complications / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D004353:Drug Evaluation, Preclinical; D005355:Fibrosis; D007249:Inflammation / Q000188:drug therapy; D007610:Kallikreins / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use*; D007668:Kidney / Q000187:drug effects* / Q000473:pathology; D007704:Kininogens / Q000378:metabolism; D008297:Male; D051379:Mice; D009569:Nitric Oxide / Q000652:urine; D018384:Oxidative Stress / Q000187:drug effects; D018002:Receptors, Bradykinin / Q000378:metabolism
chemical_list: D003029:Coagulants; D007704:Kininogens; D018002:Receptors, Bradykinin; D009569:Nitric Oxide; D003404:Creatinine; D007610:Kallikreins
keywords: diabetic nephropathy; fibrosis; inflammation; oxidative stress