Progression of tubulointerstitial injury by osteopontin-induced macrophage recruitment in advanced diabetic nephropathy of transgenic (mRen-2)27 rats.
BACKGROUND
Osteopontin is a macrophage chemotactic protein that has been pathogenetically linked to tissue injury in non-diabetic kidney disease.


METHODS
To examine osteopontin expression and macrophage accumulation in diabetic nephropathy, diabetes was induced with streptozotocin (STZ) in the transgenic (mRen-2)27 rat, a rodent model which develops the structural and functional features of its human counterpart when rendered diabetic. Non-diabetic rats were randomly selected to receive either (STZ) or citrate buffer. Diabetic rats were further randomly selected to receive either the angiotensin-converting-enzyme inhibitor, perindopril (6 mg/kg/day), or the vehicle only for 12 weeks.


RESULTS
When compared with control animals, diabetes was associated with a 10-fold increase in the gene expression of osteopontin. Increased transcript and immunostainable osteopontin were detected in tubular epithelial cells in association with extensive macrophage accumulation. Treatment with perindopril significantly ameliorated the overexpression of osteopontin in association with attenuation of macrophage accumulation.


CONCLUSIONS
These findings suggest that osteopontin expression and macrophage accumulation may play a role in the tubulointerstitial injury in diabetic nephropathy, and that inhibition of osteopontin expression may be one of the mechanisms by which blockade of the renin-angiotensin system confers a renoprotective effect.
Kelly
Darren J
DJ
Department of Medicine, University of Melbourne, St Vincent's Hospital, Fitzroy, Australia. dkelly@medstv.unimelb.edu.au
Wilkinson-Berka
Jennifer L
JL
Ricardo
Sharon D
SD
Cox
Alison J
AJ
Gilbert
Richard E
RE
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000818:Animals; D030801:Animals, Genetically Modified; D003921:Diabetes Mellitus, Experimental / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D003928:Diabetic Nephropathies / Q000473:pathology / Q000503:physiopathology*; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D007668:Kidney / Q000473:pathology*; D007684:Kidney Tubules / Q000473:pathology*; D008264:Macrophages / Q000502:physiology*; D053495:Osteopontin; D020913:Perindopril / Q000494:pharmacology; D051381:Rats; D012083:Renin / Q000235:genetics*; D012795:Sialoglycoproteins / Q000235:genetics*; D014158:Transcription, Genetic
D000806:Angiotensin-Converting Enzyme Inhibitors; C506895:SPP1 protein, human; D012795:Sialoglycoproteins; C506897:Spp1 protein, rat; D053495:Osteopontin; D012083:Renin; D020913:Perindopril