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1 Department of Cardiology and Pneumology, University Hospital Benjamin Franklin, Free University of Berlin, D-12200 Berlin; 2 Institute of Pharmacology, Christian-Albrechts University of Kiel, D-24105 Kiel; Departments of 3 Pharmacology and 4 Nephrology, University of Heidelberg, D-69115 Heidelberg; 5 Max Delbrück Center for Molecular Medicine, D-13092 Berlin; and 6 Department of Medicine/Cardiology, Virchow Klinikum, Humboldt University, D-13353 Berlin, Germany; and 7 Department of Biophysics, Federal University of São Paulo, São Paulo, Brazil
A reduction of renal kallikrein has been found in non-insulin-treated diabetic individuals, suggesting that an impaired renal kallikrein-kinin system (KKS) contributes to the development of diabetic nephropathy. We analyzed relevant components of the renal KKS in non-insulin-treated streptozotocin (STZ)-induced diabetic rats. Twelve weeks after a single injection of STZ, rats were normotensive and displayed hyperglycemia, polyuria, proteinuria, and reduced glomerular filtration rate. Blood bradykinin (BK) levels and prekallikrein activity were significantly increased compared with controls. Renal kallikrein activity was reduced by 70%, whereas urinary BK levels were increased up to threefold. Renal kininases were decreased as indicated by a 3-fold reduction in renal angiotensin-converting enzyme activity and a 1.8-fold reduction in renal expression of neutral endopeptidase 24.11. Renal cortical expression of kininogen and B2 receptors was enhanced to 1.4 and 1.8-fold, respectively. Our data suggest that increased urinary BK levels found in severely hyperglycemic STZ-diabetic rats are related to increased filtration of components of the plasma KKS and/or renal kininogen synthesis in combination with decreased renal kinin-degrading activity. Thus, despite reduced renal kallikrein synthesis, renal KKS is activated in the advanced stage of diabetic nephropathy.
diabetic nephropathy; kininogen; neutral endopeptidase 24.11; angiotensin-converting enzyme; bradykinin B2 receptor; streptozotocin
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