Loss of TIMP3 selectively exacerbates diabetic nephropathy
| Autor: | Dong Fan, George C. Liu, Subhash K. Das, James W. Scholey, Vaibhav B. Patel, Jiwon Lee, Rohan John, Zuocheng Wang, Gavin Y. Oudit, Ratnadeep Basu, Zamaneh Kassiri |
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| Jazyk: | angličtina |
| Rok vydání: | 2012 |
| Předmět: |
Male
medicine.medical_specialty endocrine system diseases Physiology ADAM17 Protein Kidney Diabetic nephropathy chemistry.chemical_compound Mice Downregulation and upregulation Diabetes mellitus Internal medicine Protein Kinase C beta Medicine Animals Diabetic Nephropathies Reactive nitrogen species Protein Kinase C Mice Knockout Tissue Inhibitor of Metalloproteinase-3 NADPH oxidase biology business.industry Kidney metabolism NADPH Oxidases Articles medicine.disease Reactive Nitrogen Species Mice Mutant Strains Mice Inbred C57BL ADAM Proteins Disease Models Animal medicine.anatomical_structure Endocrinology chemistry biology.protein Albuminuria Disease Progression medicine.symptom business |
| Popis: | Diabetic nephropathy is the most common cause of end-stage renal disease. Polymorphism in the tissue inhibitor of metalloproteinase-3 (TIMP3) gene, and the ECM-bound inhibitor of matrix metalloproteinases (MMPs), has been linked to diabetic nephropathy in humans. To elucidate the mechanism, we generated double mutant mice in which the TIMP3 gene was deleted in the genetic diabetic Akita mouse background. The aggravation of diabetic injury occurred in the absence of worsening of hypertension or hyperglycemia. In fact, myocardial TIMP3 levels were not affected in Akita hearts, and cardiac diastolic and systolic function remained unchanged in the double mutant mice. However, TIMP3 levels increased in Akita kidneys and deletion of TIMP3 exacerbated the diabetic renal injury in the Akita mouse, characterized by increased albuminuria, mesangial matrix expansion, and kidney hypertrophy. The progression of diabetic renal injury was accompanied by the upregulation of fibrotic and inflammatory markers, increased production of reactive oxygen species and NADPH oxidase activity, and elevated activity of TNF-α-converting enzyme (TACE) in the TIMP3−/−/Akita kidneys. Moreover, while the elevated phospho-Akt (S473 and T308) and phospho-ERK1/2 in the Akita mice was not detected in the TIMP3−/−/Akita kidneys, PKCβ1 (but not PKCα) was markedly elevated in the double mutant kidneys. Our data provide definitive evidence for a critical and selective role of TIMP3 in diabetic renal injury consistent with gene expression findings from human diabetic kidneys. |
| Databáze: | OpenAIRE |
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