Upregulation of osteopontin expression in renal cortex of streptozotocin-induced diabetic rats is mediated by bradykinin.
The model of streptozotocin (STZ)-induced diabetes in Wistar rats was used to study the expression of osteopontin during development of diabetic nephropathy. Diabetes was confirmed by serum glucose levels exceeding 16 mmol/l during the experimental period of 12 weeks. During this period of time, diabetic nephropathy developed, as characterized by a reduced glomerular filtration rate (2.7 +/- 0.3 ml/min in controls vs. 1.7 +/- 0.1 ml/min in diabetic rats) and proteinuria (8.3 +/- 1.7 mg/24 h in controls vs. 22.0 +/- 4 mg/24 h in diabetic rats). Northern blot analysis revealed a time-dependent upregulation of renal cortical osteopontin expression reaching 138 +/- 6% of control levels after 2 weeks and 290 +/- 30% (mean +/- SE, n = 6-9) after 12 weeks. By immunostaining, the increased osteopontin expression could be located to the tubular epithelium of the renal cortex. Chronic treatment of animals with ramipril (3 mg/kg) during the 12-week experimental period led to a further increase in osteopontin mRNA expression in diabetic animals, amounting to 570 +/- 73% (mean +/- SE, n = 6) of controls. Increased levels of osteopontin were not associated with accumulation of monocyte/macrophages that were identified by the cell type specific monoclonal antibody ED-1. The increased osteopontin expression in ramipril-pretreated rats was abolished by application of the bradykinin B2-receptor antagonist, icatibant (0.5 mg/kg). In addition, increased osteopontin expression in diabetic rats, which did not receive any treatment after STZ injection, could as well be reduced by icatibant given for the final 2 weeks of the experimental period. These data suggest that a strong bradykinin B2-receptor-mediated upregulation of osteopontin occurs during the pathogenesis of experimental diabetic nephropathy in rats.
Fischer
J W
JW
Department of Pathology, University of Washington School of Medicine, Seattle, USA. jensf@u.washington.edu
Tschöpe
C
C
Reinecke
A
A
Giachelli
C M
CM
Unger
T
T
D000818:Animals; D001920:Bradykinin / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000502:physiology*; D065168:Bradykinin Receptor Antagonists; D003921:Diabetes Mellitus, Experimental / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D003928:Diabetic Nephropathies / Q000503:physiopathology; D004848:Epithelium / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D005919:Glomerular Filtration Rate; D007672:Kidney Cortex / Q000187:drug effects / Q000378:metabolism*; D007684:Kidney Tubules / Q000378:metabolism; D008297:Male; D053495:Osteopontin; D010750:Phosphoproteins / Q000096:biosynthesis / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis; D017257:Ramipril / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D012795:Sialoglycoproteins / Q000096:biosynthesis / Q000235:genetics*; D013997:Time Factors; D014158:Transcription, Genetic / Q000187:drug effects
D065168:Bradykinin Receptor Antagonists; D010750:Phosphoproteins; D012333:RNA, Messenger; D012795:Sialoglycoproteins; C506897:Spp1 protein, rat; D053495:Osteopontin; C065679:icatibant; D017257:Ramipril; D001920:Bradykinin