title: Rosiglitazone treatment of type 2 diabetic db/db mice attenuates urinary albumin and angiotensin converting enzyme 2 excretion.
abstract: Alterations within the renal renin angiotensin system play a pivotal role in the development and progression of cardiovascular and renal disease. Angiotensin converting enzyme 2 (ACE2) is highly expressed in renal tubules and has been shown to be renoprotective in diabetes. The protease, a disintegrin and metalloprotease (ADAM) 17, is involved in the ectodomain shedding of several transmembrane proteins including ACE2. Renal ACE2 and ADAM17 were significantly increased in db/db mice compared to controls. We investigated the effect of the insulin sensitizer, rosiglitazone, on albuminuria, renal ADAM17 protein expression and ACE2 shedding in db/db diabetic mice. Rosiglitazone treatment of db/db mice normalized hyperglycemia, attenuated renal injury and decreased urinary ACE2 and renal ADAM17 protein expression. Urinary excreted ACE2 is enzymatically active. Western blot analysis of urinary ACE2 demonstrated two prominent immunoreactive bands at approximately 70 & 90 kDa. The predominant immunoreactive band is approximately 20 kDa shorter than the one demonstrated for kidney lysate, indicating possible ectodomain shedding of active renal ACE2 in the urine. Therefore, it is tempting to speculate that renoprotection of rosiglitazone could be partially mediated via downregulation of renal ADAM17 and ACE2 shedding. In addition, there was a positive correlation between blood glucose, urinary albumin, plasma glucagon, and triglyceride levels with urinary ACE2 excretion. In conclusion, urinary ACE2 could be used as a sensitive biomarker of diabetic nephropathy and for monitoring the effectiveness of renoprotective medication.
authors: Department of Pharmacology and Toxicology, Boonshoft School of Medicine, Wright State University, Dayton, Ohio, United States of America.
authors: Harshita
authors: H
authors: Chodavarapu
authors: Nadja
authors: N
authors: Grobe
authors: Hari K
authors: HK
authors: Somineni
authors: Esam S B
authors: ES
authors: Salem
authors: Malav
authors: M
authors: Madhu
authors: Khalid M
authors: KM
authors: Elased
mesh_terms: D051722:ADAM Proteins / Q000378:metabolism; D000072198:ADAM17 Protein; D000419:Albuminuria / Q000652:urine*; D000085962:Angiotensin-Converting Enzyme 2; D000818:Animals; D001786:Blood Glucose / Q000187:drug effects; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy / Q000378:metabolism / Q000652:urine*; D004195:Disease Models, Animal; D005934:Glucagon / Q000097:blood; D005951:Glucose Tolerance Test; D006029:Glycosuria; D006943:Hyperglycemia / Q000188:drug therapy; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D007674:Kidney Diseases / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism / Q000652:urine*; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000008:administration & dosage / Q000494:pharmacology*; D019717:Tissue Inhibitor of Metalloproteinase-3 / Q000378:metabolism; D014280:Triglycerides / Q000097:blood
chemical_list: D001786:Blood Glucose; D007004:Hypoglycemic Agents; D008565:Membrane Proteins; D045162:Thiazolidinediones; D019717:Tissue Inhibitor of Metalloproteinase-3; D014280:Triglycerides; C113267:nephrin; D000077154:Rosiglitazone; D005934:Glucagon; D007703:Peptidyl-Dipeptidase A; C000705328:Ace2 protein, mouse; D000085962:Angiotensin-Converting Enzyme 2; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606463:Adam17 protein, mouse
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