Interstitial expression of angiotensin II and AT1 receptor are increased in patients with progressive glomerulopathies

Abstract

In animal models, interstitial angiotensin II (ang II) and AT1 receptor (AT1R) are key mediators of renal inflammation and fibrosis in progressive chronic nephropathies. We hypothesized that these molecules were overexpressed in patients with progressive glomerulopathies. In this observational retrospective study, we described the expression of ang II and AT1R by immunohistochemistry in kidney biopsies of 7 patients with minimal change disease (MCD) and in 25 patients with progressive glomerulopathies (PGPs). Proteinuria, serum albumin, and serum creatinine were not statistically different between MCD and PGP patients. Total expression of ang II and AT1R was not statistically different between MCD (108.7±11.5 and 73.2±13.6 cells/mm², respectively) and PGN patients (100.7±9.0 and 157.7±13.8 cells/mm², respectively; p>0.05). Yet, interstitial expression of ang II and AT1R (91.6±16.0 and 45.6±5.4 cells/mm², respectively) was higher in patients with PGN than in those with MCD (22.0±4.1 and 17.9±2.9 cells/mm², respectively, p<0.05), as was the proportion of interstitial fibrosis (11.0±0.7% versus 6.1±1.2%, p<005). In patients with MCD, ang II and AT1R expressions predominate in the tubular compartment (52% and 36% of the positive cells, respectively). In those with PGP, the interstitial expression of ang II and AT1R predominates (58% and 45%, respectively). In conclusion, interstitial expression of ang II and AT1R is increased in patients with progressive glomerulopathies. The relationship of these results and interstitial fibrosis and disease progression in humans warrants further investigations.

Keywords

angiotensin II AT1 receptor glomerulonephritis glomerulopathy proteinuria

Get full access to this article

View all access options for this article.

References

Warnock DG Prevention, protection, and the intrarenal renin-angiotensin systems . Semin Nephrol 2001; 21: 593-602.

Zatz R.

Haemodynamically mediated glomerular injury: the end of a 15-year-old controversy?

Curr Opin Nephrol Hypertens 1996;5:468-470.

Böttinger EP , Bitzer M. TGF-β signaling in renal disease . J Am Soc Nephrol 2002;13 2600-2610.

Abbate M. , Zoja C. , Rottoli D. , Corna D. , Tomasoni S. , Remuzzi G. Proximal tubular cells promote fibrogenesis by TGF-β1-mediated induction of peritubular myofibroblasts. Kidney Int 2002;61:2066-2077.

Velez JC The importance of the intrarenal renin-angiotensin system. Nat Clin Pract Nephrol 2009;5:89-100.

Agarwal R. , Siva S. , Dunn S. , Sharma K. Add-on angiotensin II receptor blockade lowers urinary transforming growth factor-β levels. Am J Kidney Dis 2002;39:486-492.

Suzuki Y. , Ruiz-Ortega M. , Gomez-Guerrero C. , Tomino Y. , Egido J. Angiotensin II , the immune system and renal diseases: another road for RAS? Nephrol Dial Transplant 2003; 18:1423-1426.

Ardaillou R. Angiotensin II-complexities beyond AT1 and AT2 receptors. Nephrol Dial Transplant 1998 ;13:2988-2990.

Maschio G. , Alberti D. , Janin G. , Locatelli F. , Mann JFE , Matolese M. , et al. Effect of angiotensin-enzyme inhibitor benazepril on the progression of chronic renal insufficiency. The Angiotensin-Converting-Enzyme Inhibition in Progressive Renal Insufficiency Study Group. N Engl J Med 1996;334: 939-945.

10.

Ruggenenti P. , Perna A. , Gherardi G. , Gaspari F. , Benini T. , 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;352:1252-1256.

11.

Kshirsagar AV , Joy MS , Hogan SL , Falk RJ , Colindres RE Effect of ACE inhibitors in diabetic and nondiabetic chronic renal disease: a systematic overview of randomized placebo-controlled trials. Am J Kidney Dis 2000;35:695-707.

12.

Gonçalves AR , Fujihara CK , Mattar AL , Malheiros DMA , Noronha IL , de Nucci G. , et al. Renal expression of COX-2, ANG II, and AT1 receptor in remnant kidney: strong renoprotection by therapy with losartan and a nonsteroidal antiinflammatory. Am J Physiol Renal Physiol 2004;286:F945-F954.

13.

Graciano ML , Cavaglieri RC , Dellê H. , Dominguez WV , Casarini DE , Malheiros DMA , et al. Intrarenal renin-angiotensin system is unregulated in experimental model of progressive renal disease induced by chronic inhibition of nitric oxide synthesis . J Am Soc Nephrol 2004;15:1805-1815.

14.

Franco M. , Martínez F. , Quiroz Y. , Galicia O. , Bautista R. , Johnson RJ , Rodríguez-Iturbe B. Renal angiotensin II concentration and interstitial infiltration of immune cells are correlated with blood pressure levels in salt-sensitive hypertension . Am J Physiol Regul Integr Comp Physiol 2007 ;293:R251-R256.

15.

Arima S. , Ito S. New insights into actions of the renin- angiotensin system in the kidney: concentrating on the ang II receptors and the newly described ang-(1-7) and its receptor. Semin Nephrol 2001;21:535-543.

16.

Matsubara H. , Sugaya T. , Murasawa S. , Nozawa Y. , Mori Y. , Masaki H. , et al. Tissue-specific expression of human angiotensin II AT1 and AT2 receptors and cellular localization of subtype mRNAs in adult human renal cortex using in situ hybridization. Nephron 1998;80:25-34.

17.

Fujihara C. , Noronha IL , Malheiros DMA , Antunes GR , Oliveira IB , Zatz R. Combined mycophenolate mofetil and losartan therapy arrests established injury in the remnant kidney . J Am Soc Nephrol 2000;11:283-290.

18.

Benigni A. , Gagliardini E. , Remuzzi G. Changes in glomerular perm-selectivity induced by angiotensin II imply podocyte dysfunction and slit diaphragm protein rearrangement. Semin Nephrol 2004;24:131-140.

19.

Navar G. , Lewis L. , Hymel A. , Braam B. , Mitchell KD Tubular fluid concentrations and kidney contents of angiotensins I and II in anesthetized rats. J Am Soc Nephrol 1994 ; 5:1153-1158.

20.

Navar LG , Harrison-Bernard LM , Nishiyama A. , Koburi H. Regulation of intrarenal angiotensin II in hypertension. Hypertension 2002;39:316-322.

21.

Nishiyama A. , Seth DM , Navar G. Renal interstitial fluid concentrations of angiotensins I and II in anesthetized rats. Hypertension 2002;39:129-134.

22.

Price D. , Porter L. , Gordon M. , Fisher NDL , De’Oliveira JMF , Laffel LMB , et al. The paradox of the low-renin state in diabetic nephropathy. J Am Soc Nephrol 1999;10:2382-2391.

23.

Campbell DJ , Lawrence AC , Towrie A. , Kladis A. , Valentijn AJ Differential regulation of angiotensin peptide levels in plasma and kidney of the rat. Hypertension 1991;18:763-773.

24.

Zatz, R. Fujihara CK Mechanisms of progressive renal disease: role of angiotensin II, cyclooxygenase products and nitric oxide. J Hypertens 2002 ;20(Suppl 3):S37-S44.

25.

Mezzano S. , Aros CA , Droguett A. , Burgos ME , Ardiles LG , Flores CA , et al. Renal angiotensin II up-regulation and myofibroblast activation in human membranous nephropathy. Kidney Int 2003;64(Suppl 86):S39-S45.

26.

Mifune M. , Sasamura H. , Nakazato Y. , Yamaji Y. , Ashima N. , Sakita T. Examination of angiotensin II type 1 and type 2 receptor expression in human kidneys by immunohistochemistry. Clin Exp Hypertens 2001;23:257-266.

27.

Wagner J. , Gehlen F. , Ciecnhanowicz A. , Ritz E. Angiotensin II receptor type 1 gene expression in human glomerulonephritis and Diabetes Mellitus. J Am Soc Nephrol 1999 ;10:545-551.