Perindopril attenuates tubular hypoxia and inflammation in an experimental model of diabetic nephropathy in transgenic Ren-2 rats.
BACKGROUND
Renal hypoxia plays a role in the development of diabetic nephropathy, and may be mediated by overactivity of the renin-angiotensin-aldosterone system (RAAS). In this study the localization of cellular hypoxia in an experimental model of diabetic nephropathy was assessed, and the effect of the angiotensin-converting enzyme inhibitor perindopril on hypoxia evaluated.


METHODS
Female Sprague-Dawley rats heterozygous for the Ren-2 gene were randomized to three groups (n = 8 per group)--controls, diabetes or diabetes + perindopril. Diabetes was induced by injection of streptozotocin at 6 weeks of age. Perindopril was administered at a dose of 2 mg/kg daily from 6 weeks. Subjects were culled after 16 weeks. Areas of tissue hypoxia were localized using immunohistochemistry to detect pimonidazole uptake.


RESULTS
Diabetic rat kidneys were characterized by increases in tubulointerstitial collagen deposition compared with controls. Tubular hypoxia was significantly greater in diabetic rats, indicated by a 2.5-fold increase in the proportional area of pimonidazole immunostaining (P < 0.001). Immunohistochemical staining for pimonidazole co-localized with osteopontin, and was associated with higher numbers of ED-1-positive cells (macrophages) within the tubulointerstitium. Treatment with perindopril ameliorated structural changes of diabetic nephropathy and reduced the amount of pimonidazole and ED-1 immunostaining to levels similar to that of controls.


CONCLUSIONS
In diabetic Ren-2 rats the development of diabetic nephropathy was associated with tubular hypoxia. Co-localization of osteopontin with hypoxic cells suggests that tubular hypoxia may be involved in the pathogenesis of diabetic nephropathy. The degree of hypoxia and fibrosis was attenuated by treatment with perindopril.
Wiggins
Kathryn J
KJ
Department of Medicine, The University of Melbourne, St Vincent's Hospital, Melbourne, Victoria, Australia. kate.wiggins@svhm.org.au
Tiauw
Victoria
V
Zhang
Yuan
Y
Gilbert
Richard E
RE
Langham
Robyn G
RG
Kelly
Darren J
DJ
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000150:complications* / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism; D003928:Diabetic Nephropathies / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism; D005260:Female; D005355:Fibrosis; D000860:Hypoxia / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism; D007150:Immunohistochemistry / Q000379:methods; D007249:Inflammation / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism; D007684:Kidney Tubules / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D009593:Nitroimidazoles; D053495:Osteopontin / Q000378:metabolism; D020913:Perindopril / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D055647:Rats, Transgenic; D012083:Renin / Q000235:genetics / Q000378:metabolism*; D012084:Renin-Angiotensin System / Q000187:drug effects; D013997:Time Factors
D000806:Angiotensin-Converting Enzyme Inhibitors; D009593:Nitroimidazoles; C473112:Ren2 protein, mouse; C506897:Spp1 protein, rat; D053495:Osteopontin; C033815:pimonidazole; D012083:Renin; D020913:Perindopril