Involvement of renal ACE activity in proteinuria-associated renal damage in untreated and treated adriamycin nephrotic rats

Abstract

Proteinuria is assumed to play a pathogenetic role in progressive renal damage. Angiotensin-converting enzyme (ACE) inhibition reduces proteinuria and provides renoprotection. This suggests that ACE activity might play a pathogenetic role in the development of proteinuria-induced renal structural damage. We investigated this hypothesis in untreated and treated established adriamycin nephrosis, a model of proteinuria-induced renal damage.

In a time-course experiment, the development of renal structural damage in untreated adriamycin nephrotic rats was paralleled by a significant rise in renal ACE activity. Moreover, on cross-sectional analysis, a consistent positive correlation between renal, but not plasma, ACE activity and proteinuria, focal glomerulosclerosis and interstitial injury was present. Notably, these associations were present, not only in the untreated condition, but also during intervention with either ACE inhibition or AT₁-receptor antagonism. Interestingly, we found that higher renal ACE activity is associated with more severe renal damage for a given amount of proteinuria, suggesting that renal ACE activity may be either a permissive or a promoting factor in the processes by which proteinuria eventually leads to renal structural damage. This relationship was abolished by renin-angiotensin system (RAS)-blockade, suggesting that RAS-mediated effects are involved in the relationship between renal ACE activity and proteinuria-induced renal damage.

In conclusion, in untreated as well as treated adriamycin nephrotic rats, renal ACE activity is closely associated with renal outcome. This association appears to be independent of the specific mode of blockade of the RAS. Renal ACE activity is a consistent marker of individual differences in proteinuria-associated renal damage: further studies are needed to investigate a possible pathogenetic role in renal damage.

Keywords

renal ACE proteinuria treatment ACE inhibition

Get full access to this article

View all access options for this article.

References

Remuzzi G. , Bertani T.

Is glomerulosclerosis a consequence of altered glomerular permeability to macromolecules?

Kidney Int 1990;38:384-94.

Wapstra FH , Van Goor H. , Navis GJ , De Jong PE , De Zeeuw D. Antiproteinuric effect predicts renal protection by angiotensin-converting enzyme inhibition in rats with established adriamycin nephrosis. Clin Sci (Colch) 1996;90:393-401.

Abbate M. , Remuzzi G. Proteinuria as a mediator of tubulointerstitial injury. Kidney Blood Press Res 1999;22:37-46.

Wapstra FH , Navis GJ , De Jong PE , De Zeeuw D. Prognostic value of the short-term antiproteinuric response to ACE inhibition for prediction of GFR decline in patients with nondiabetic renal disease. Exp Nephrol 1996;4(suppl 1):47-52.

Apperloo AJ , De Zeeuw D. , De Jong PE Short-term antiproteinuric response to antihypertensive treatment predicts long-term GFR decline in patients with non-diabetic renal disease . Kidney Int 1994;(suppl 45):S174-S178.

Ruggenenti P. , Perna A. , Gherardi G. , Gaspari F. , Benini R. , Remuzzi G. Renal function and requirement for dialysis in chronic nephropathy patients on long-term ramipril: REIN follow-up trial. Gruppo Italiano di Studi Epidemiologici in Nefrologia (GISEN). Ramipril Efficacy in Nephropathy. Lancet 1998;352:1252-6.

Apperloo AJ , De Zeeuw D. , Sluiter HE , De Jong PE Differential effects of enalapril and atenolol on proteinuria and renal haemodynamics in non-diabetic renal disease. BMJ 1991;303:821-4.

Largo R. , Gómez-Garre D. , Soto K. et al. Angiotensin-converting enzyme is upregulated in the proximal tubules of rats with intense proteinuria. Hypertension 1999;33:732-9.

Wapstra FH , Van Goor H. , De Jong PE , Navis GJ , De Zeeuw D. Dose of doxorubicin determines severity of renal damage and responsiveness to ACE-inhibition in experimental nephrosis. J Pharmacol Toxicol Methods 1999;41:69-73.

10.

De Boer E. , Navis GJ , Tiebosch Atmg , De Jong PE , De Zeeuw D. Systemic factors are involved in the pathogenesis of proteinuria-induced glomerulosclerosis in adriamycin nephrotic rats. J Am Soc Nephrol 1999;10:2359-66.

11.

Wapstra FH , Navis GJ , De Jong PE , De Zeeuw D. Chronic angiotensin II infusion but not bradykinin blockade abolishes the antiproteinuric response to angiotensin-converting enzyme inhibition in established adriamycin nephrosis. J Am Soc Nephrol 2000 ;11:490-6.

12.

Van Goor H. , Van der Horst ML , Fidler V. , Grond J. Glomerular macrophage modulation affects mesangial expansion in the rat after renal ablation. Lab Invest 1992;66:564-71.

13.

Raij L. , Azar S. , Keane W. Mesangial immune injury, hypertension, and progressive glomerular damage in Dahl rats. Kidney Int 1984;26:137-43.

14.

Hirsch AT , Talsness CE , Schunkert H. , Paul M. , Dzau VJ Tissue-specific activation of cardiac angiotensin converting enzyme in experimental heart failure. Circ Res 1991;69:475-82.

15.

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 Pharmacol 1997;29:684-91.

16.

Bland M. An introduction to medical statistics. Oxford: Oxford University Press, 1987; pp 98-101.

17.

Venkatesan N. , Ramesh CV , Jayakumar R. , Chandrakasan G. Angiotensin I converting enzyme activity in adriamycin induced nephrosis in rats. Toxicology 1993;85:137-48.

18.

Bertani T. , Rocchi G. , Sacchi G. , Mecca G. , Remuzzi G. Adriamycin-induced glomerulosclerosis in the rat. AmJKidney Dis 1986;7:12-19.

19.

Metzger R. , Bohle RM , Pauls K. et al.Angiotensin-converting enzyme in non-neoplastic kidney diseases . Kidney Int 1999; 56:1442-54.

20.

Hollenberg NK ACE inhibitors, AT1 receptor blockers, and the kidney (editorial). Nephrol Dial Transplant 1997;12: 381-3.

21.

Morishita R. , Gibbons GH , Ellison KE et al. Evidence for direct local effect of angiotensin in vascular hypertrophy. In vivo gene transfer of angiotensin converting enzyme. J Clin vivo gene transfer of angiotensin converting enzyme. J Clin Invest 1994;94:978-84.