Restricted accessOtherFirst published online 2002-03
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.
Conclusion In conclusion, intrarenal levels of ACE may play a role in the development of renal damage in experimental chronic renal transplant failure.
Paul LCGlomerular hypertension- an under-appreciated aspect of chronic rejection . Nephrol Dial Transplant2001;16:213-99.
3.
Dimeney E., Wahlberg J., Lithell H., Fellstrom B.Hyperlipidemia in renal transplantation. Risk factor for long-term graft outcome . Eur J Clin Invest1995;25:574-83.
4.
Roodnat JI, Mulder PG, Rischen-Vos J. et al. Proteinuria and death risk in the renal transplant population . Transplant Proc2001;33:1170-1.
5.
Mackenzie HS , Azuma H., Rennke HG, Tilney NL, Brenner BMRenal mass as a determinant of late allograft outcome:insights from experimental studies in rats. Kidney Int1995;52(suppl):S38-S42.
6.
Ziai F., Ots M., Provoost AP et al.The angiotensin receptor antagonist, irbesartan, reduces renal injury in experimental chronic renal failure. Kidney Int1996;57(suppl):pS132-S136.
7.
Liu S., Lutz J., Antus B., Yao Y., Baik S., Illies F., Heemann U.Recipient age and weight affect chronic renal allograft rejection in rats . J Am Soc Nephrol2001;12:1742-9.
8.
Smit-van Oosten A., Navis G., Stegeman CA et al. Chronic blockade of angiotensin II action prevents glomerulosclerosis, but induces graft vasculopathy in experimental kidney transplantation. J Pathol2001;194:122-9.
9.
Paul LCExperimental models of chronic renal allograft rejection. Transplant Proc1995;27:2126-8.
10.
Kingma I., Chea R., Davidoff A., Benediktsson H., Paul LCGlomerular capillary pressures in long-surviving rat renal allografts. Transplantation1993;56:53-60.
11.
Benediktsson H., Chea R., Davidoff A., Paul LCAntihypertensive drug treatment in chronic renal allograft rejection in the rat. Transplantation1996;62:1634-42.
12.
Metzger R., Bohle RM, Pauls K. et al.Angiotensin-converting enzyme in non-neoplastic kidney diseases . Kidney Int1999;56:1442-54.
13.
McLaughlin KJ, Harden PN, Ueda S., Boulton-Jones JM, Connell JM, Jardine AGThe role of genetic polymorphisms of angiotensin-converting enzyme in the progression of renal diseases.Hypertension1996;28:912-15.
14.
Yoshida H., Mitarai T., Kawamura T. et al. Role of the deletion of polymorphism of the angiotensin converting enzyme gene in the progression and therapeutic responsiveness of IgA nephropathy . J Clin Invest1995;96:2162-9.
15.
Harden PN, Geddes C., Rowe PA et al. Polymorphisms in angiotensin-converting-enzyme gene and progression of IgA nephropathy. Lancet1995;345:1540-2.
16.
Marre M., Bernadet P., Gallois Y. et al. Relationships between angiotensin I converting enzyme gene polymorphism, plasma levels, and diabetic retinal and renal complications. Diabetes1994;43:384-8.
17.
Mizuiri S., Hemmi H., Inoue A. et al.Angiotensin-converting enzyme polymorphism and development of diabetic nephropathy in non-insulin-dependent diabetes mellitus. Nephron1995;70:455-9.
18.
Jeffers BW, Estacio RO, Raynolds MV, Schrier RWAngiotensin-converting enzyme gene polymorphism in non-insulin dependent diabetes mellitus and its relationship with diabetic nephropathy. Kidney Int1997;52:473-7.
19.
Yoshida H., Kuriyama S.,Atsumi Y. et al. Angiotensin I converting enzyme gene polymorphism in non-insulin dependent diabetes mellitus. Kidney Int1996 ;50:657-64.
20.
Barocci S., Ginevri F., Valente U.,Torre F., Gusmano R., Nocera A.Correlation between angiotensin-converting enzyme gene insertion/deletion polymorphism and kidney graft long-term outcome in pediatric recipients: a single-center analysis. Transplantation1999 ;67:534-8.
21.
Abdi R., Tran TB, Zee R., Brenner BM, Milford ELAngiotensin gene polymorphism as a determinant of post-transplantation renal dysfunction and hypertension. Transplantation2001;72:726-9.
22.
Beige J., Offermann G., Distler A., Sharma AMAngiotensin-converting-enzyme insertion/deletion genotype and long-term renal allograft survival. Nephrol Dial Transplant1998;13:735-8.
23.
Siegl PK, Chang RS, Mantlo NB et al. In vivo pharmacology of L-158,809, a new highly potent and selective nonpeptide angiotensin II receptor antagonist. J Pharmacol Exp Ther1992;262:133-8.
24.
Hirsch AT, Talsness CE, Schunkert H., Paul M., Dzau VJTissue-specific activation of cardiac angiotensin converting enzyme in experimental heart failure. Circ Res1991;69:475-82.
25.
Buikema H., Pinto YM, van Geel PP et al. Differential inhibition of plasma versus tissue ACE by utibapril:biochemical and functional evidence for inhibition of vascular ACE activity. J Cardiovasc Pharmacol1997;29:684-91.
26.
Chomczynski P. , Sacchi N.Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem1987;162:156-9.
27.
Brundel Bjjm , van Gelder IC, Henning et al. Gene expression of proteins influencing the calcium homeostasis in patients with persistent and paroxysmal atrial fibrillation. Cardiovasc Res1999;42:443-54.
28.
Pastore L.,TessitoreA.,Martinotti S. et al.Angiotensin II stimulates intercellular adhesion molecule-1 (ICAM-1) expression by human vascular endothelial cells and increases soluble ICAM-1 release in vivo. Circulation1999;100:1646-52.
29.
Ruiz-Ortega M. , Bustos C., Hernandez-Presa MA, Lorenzo O., Plaza JJ, Egido J.Angiotensin II participates in mononuclear cell recruitment in experimental immune complex nephritis through nuclear factor-kappa B activation and monocyte chemoattractant protein-1 synthesis . J Immunol1998; 161:430-9.
30.
Fogo ABThe role of angiotensin II and plasminogen activator inhibitor-1 in progressive glomerulosclerosis. Am J Kidney Dis2000;35:179-88.
31.
De Heer E., Prodjosudjadi W., Davidoff A., van der Wal A., Bruijn JA, Paul LCControl of monocyte influx in glomerulonephritis in transplanted kidneys in the rat. Lab Invest1998;78:1327-37.
32.
Zhuo JLRenomedullary interstitial cells: a target for endocrine and paracrine actions of vasoactive peptides in the renal medulla. Clin Exp Pharmacol Physiol2000;27:465-73.
33.
Largo R., Gomez-Garre D., Soto K. et al. Angiotensin-converting enzyme is upregulated in the proximal tubules of rats with intense proteinuria. Hypertension1999;33:732-9.
