Strain differences in angiotensin-converting enzyme and angiotensin II type I receptor expression. Possible implications for experimental chronic renal transplant failure.
BACKGROUND
The Fisher to Lewis (F-L) model of renal transplantation (Rtx) is widely used. Rtx from F to L without immunosuppressive treatment results in 50% survival, whereas L to F results in survival rates similar to syngrafts. When treated with an angiotensin-converting enzyme (ACE) inhibitor or antihypertensive triple therapy, renal damage is markedly reduced in F-L allografts. Despite similar reductions in blood pressure, the ACE inhibitor (ACE-I) is more effective than antihypertensive triple therapy, suggesting that the inhibition of intrarenal ACE plays an additional role in the attenuation of renal damage.


METHODS
In the present study, we investigated strain-related differences in intrarenal ACE activity between F and L rats and whether treatment with ACE-I in F-L allografted rats results in reduction of intrarenal ACE. Intrarenal ACE was measured by activity assays, immunohistochemistry and PCR.


RESULTS
In control kidneys from healthy F rats (n=8), we found a four-fold higher ACE activity than in native L rats (n=8, p<0.01). This was confirmed by a three-fold difference in ACE mRNA expression (n=5 for both, p<0.01). Using immunohistochemistry, we found strong tubular ACE expression in the F rat, whereas the L rat had no tubular ACE at all. In F-L allografts (n=9) we noted significant glomerulosclerosis and proteinuria after 34 weeks. Treatment with ACE-I in F-L (n=8) prevented the development of these changes. Although ACE mRNA and ACE protein expression were similar in treated and untreated allografts, intrarenal ACE activity was reduced by 50% in allografts with ACE-I.


CONCLUSIONS
In conclusion, intrarenal levels of ACE may play a role in the development of renal damage in experimental chronic renal transplant failure.
Smit-van Oosten
Annemieke
A
Department of Pathology and Laboratory Medicine, University Hospital Groningen, The Netherlands. a.smit-van.oosten@med.rug.nl
Henning
Robert H
RH
van Goor
Harry
H
D000818:Animals; D007150:Immunohistochemistry; D007668:Kidney / Q000473:pathology; D016030:Kidney Transplantation / Q000473:pathology / Q000502:physiology*; D008297:Male; D007703:Peptidyl-Dipeptidase A / Q000096:biosynthesis* / Q000235:genetics*; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D011916:Rats, Inbred F344; D011917:Rats, Inbred Lew; D044140:Receptor, Angiotensin, Type 1; D011945:Receptors, Angiotensin / Q000096:biosynthesis* / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013045:Species Specificity
D012333:RNA, Messenger; D044140:Receptor, Angiotensin, Type 1; D011945:Receptors, Angiotensin; D007703:Peptidyl-Dipeptidase A