Produção Nacional
Revisado por pares
Regression of glomerular injury by losartan in experimental diabetic nephropathy
2008; Elsevier BV; Volume: 75; Issue: 1 Linguagem: Inglês
10.1038/ki.2008.528
ISSN1523-1755
AutoresFlávio Teles, Flávia G. Machado, Bianca Helena Ventura Fernandes, Denise Maria Avancini Costa Malheiros, Clarice Kazue Fujihara, Luiz Fernando Ferraz da Silva, Roberto Zatz,
Tópico(s)Renal Diseases and Glomerulopathies
ResumoMany features of chronic kidney disease may be reversed, but it is unclear whether advanced lesions, such as adhesions of sclerotic glomerular tufts to Bowman's capsule (synechiae), can resolve during treatment. We previously showed, using a renal ablation model, that the renoprotective effect of the AT-1 receptor blocker, losartan, is dose-dependent. Here we determined if moderate and advanced glomerular lesions, associated with streptozotocin-induced diabetes, regress with conventional or high-dose losartan treatment. Using daily insulin injection for 10 months, we maintained diabetic adult male Munich-Wistar rats in a state of moderate hyperglycemia. Following this period, some rats continued to receive insulin with or without conventional or high-dose losartan for an additional 2 months. Diabetic rats pretreated with insulin for 10 months and age-matched non-diabetic rats served as controls. Mesangial expansion was found in the control diabetic rats and was exacerbated in those rats maintained on only insulin for an additional 2 months. Conventional and high-dose losartan treatments reduced this mesangial expansion and the severity of synechiae lesions below that found prior to treatment; however, the frequency of the latter was unchanged. There was no dose–response effect of losartan. Our results show that regression of mesangial expansion and contraction of sclerotic lesions is feasible in the treatment of diabetes, but complete resolution of advanced glomerulosclerosis may be hard to achieve. Many features of chronic kidney disease may be reversed, but it is unclear whether advanced lesions, such as adhesions of sclerotic glomerular tufts to Bowman's capsule (synechiae), can resolve during treatment. We previously showed, using a renal ablation model, that the renoprotective effect of the AT-1 receptor blocker, losartan, is dose-dependent. Here we determined if moderate and advanced glomerular lesions, associated with streptozotocin-induced diabetes, regress with conventional or high-dose losartan treatment. Using daily insulin injection for 10 months, we maintained diabetic adult male Munich-Wistar rats in a state of moderate hyperglycemia. Following this period, some rats continued to receive insulin with or without conventional or high-dose losartan for an additional 2 months. Diabetic rats pretreated with insulin for 10 months and age-matched non-diabetic rats served as controls. Mesangial expansion was found in the control diabetic rats and was exacerbated in those rats maintained on only insulin for an additional 2 months. Conventional and high-dose losartan treatments reduced this mesangial expansion and the severity of synechiae lesions below that found prior to treatment; however, the frequency of the latter was unchanged. There was no dose–response effect of losartan. Our results show that regression of mesangial expansion and contraction of sclerotic lesions is feasible in the treatment of diabetes, but complete resolution of advanced glomerulosclerosis may be hard to achieve. In recent years, the concept that regression of chronic kidney disease (CKD) can be achieved has been intensely discussed.1.Adamczak M. Gross M.L. Krtil J. et al.Reversal of glomerulosclerosis after high-dose enalapril treatment in subtotally nephrectomized rats.J Am Soc Nephrol. 2003; 14: 2833-2842Crossref PubMed Scopus (145) Google Scholar, 2.Boffa J.J. Lu Y. Placier S. et al.Regression of renal vascular and glomerular fibrosis: role of angiotensin II receptor antagonism and matrix metalloproteinases.J Am Soc Nephrol. 2003; 14: 1132-1144Crossref PubMed Scopus (173) Google Scholar, 3.Fioretto P. Steffes M.W. Sutherland D.E. et al.Reversal of lesions of diabetic nephropathy after pancreas transplantation.N Engl J Med. 1998; 339: 69-75Crossref PubMed Scopus (953) Google Scholar, 4.Ma L.J. Nakamura S. Aldigier J.C. et al.Regression of glomerulosclerosis with high-dose angiotensin inhibition is linked to decreased plasminogen activator inhibitor-1.J Am Soc Nephrol. 2005; 16: 966-976Crossref PubMed Scopus (126) Google Scholar, 5.Remuzzi A. Gagliardini E. Donadoni C. et al.Effect of angiotensin II antagonism on the regression of kidney disease in the rat.Kidney Int. 2002; 62: 885-894Abstract Full Text Full Text PDF PubMed Scopus (75) Google Scholar, 6.Takahashi H. Ichihara A. Kaneshiro Y. et al.Regression of nephropathy developed in diabetes by (Pro)renin receptor blockade.J Am Soc Nephrol. 2007; 18: 2054-2061Crossref PubMed Scopus (119) Google Scholar This exciting possibility was first shown in concrete terms by Fioretto et al.3.Fioretto P. Steffes M.W. Sutherland D.E. et al.Reversal of lesions of diabetic nephropathy after pancreas transplantation.N Engl J Med. 1998; 339: 69-75Crossref PubMed Scopus (953) Google Scholar, who described regression of moderate diabetic glomerulopathy 10 years after pancreatic transplantation. More recently, several studies utilizing experimental models of diabetic and nondiabetic CKD have provided additional evidence that continuous suppression of the renin–angiotensin system (RAS) with angiotensin I-converting enzyme inhibitors or angiotensin II (Ang II) receptor blockers can not only detain but even revert progressive renal injury.1.Adamczak M. Gross M.L. Krtil J. et al.Reversal of glomerulosclerosis after high-dose enalapril treatment in subtotally nephrectomized rats.J Am Soc Nephrol. 2003; 14: 2833-2842Crossref PubMed Scopus (145) Google Scholar, 2.Boffa J.J. Lu Y. Placier S. et al.Regression of renal vascular and glomerular fibrosis: role of angiotensin II receptor antagonism and matrix metalloproteinases.J Am Soc Nephrol. 2003; 14: 1132-1144Crossref PubMed Scopus (173) Google Scholar However, interpretation of these observations is often clouded by the lack of a precise definition of the attending lesions. The term ‘glomerulosclerosis’ (GS) is utilized in a somewhat loose manner, and may refer to an ample spectrum of glomerular lesions, ranging from simple deposition of extracellular matrix at the mesangial area to severe occlusion of capillary loops with formation of synechiae with Bowman's capsule. Irrespective of nomenclature, it is presently unclear whether more ‘advanced’ lesions can regress, or whether reversal of injury is instead restricted to those situations involving only relatively ‘moderate’ lesions such as mesangial expansion. This aspect acquires special importance whereas recent evidence indicates that a substantial fraction of diabetic patients with microalbuminuria but not overt proteinuria exhibit nevertheless decreased renal function and/or subsequent progression to severe CKD, suggesting that ‘advanced’ injury might already be present in a large fraction of glomeruli even in apparently incipient diabetic nephropathy.7.Perkins B.A. Ficociello L.H. Ostrander B.E. et al.Microalbuminuria and the risk for early progressive renal function decline in type 1 diabetes.J Am Soc Nephrol. 2007; 18: 1353-1361Crossref PubMed Scopus (283) Google Scholar, 8.Kriz W. LeHir M. Pathways to nephron loss starting from glomerular diseases—insights from animal models.Kidney Int. 2005; 67: 404-419Abstract Full Text Full Text PDF PubMed Scopus (349) Google Scholar A more precise knowledge of which lesions are indeed reversible is therefore highly desirable. It is now well established that therapy with angiotensin I-converting enzyme inhibitors and/or Ang II receptor blockers has strategic importance in the clinical management of CKD. However, it is currently unclear whether higher-than-usual doses of these compounds are necessary to promote renoprotection and, especially, regression of chronic renal injury. A number of experimental1.Adamczak M. Gross M.L. Krtil J. et al.Reversal of glomerulosclerosis after high-dose enalapril treatment in subtotally nephrectomized rats.J Am Soc Nephrol. 2003; 14: 2833-2842Crossref PubMed Scopus (145) Google Scholar, 4.Ma L.J. Nakamura S. Aldigier J.C. et al.Regression of glomerulosclerosis with high-dose angiotensin inhibition is linked to decreased plasminogen activator inhibitor-1.J Am Soc Nephrol. 2005; 16: 966-976Crossref PubMed Scopus (126) Google Scholar, 9.Yu C. Gong R. Rifai A. et al.Long-term, high-dosage candesartan suppresses inflammation and injury in chronic kidney disease: nonhemodynamic renal protection.J Am Soc Nephrol. 2007; 18: 750-759Crossref PubMed Scopus (44) Google Scholar and clinical10.Aranda P. Segura J. Ruilope L.M. et al.Long-term renoprotective effects of standard versus high doses of telmisartan in hypertensive nondiabetic nephropathies.Am J Kidney Dis. 2005; 46: 1074-1079Abstract Full Text Full Text PDF PubMed Scopus (58) Google Scholar, 11.Rossing K. Schjoedt K.J. Jensen B.R. et al.Enhanced renoprotective effects of ultrahigh doses of irbesartan in patients with type 2 diabetes and microalbuminuria.Kidney Int. 2005; 68: 1190-1198Abstract Full Text Full Text PDF PubMed Scopus (194) Google Scholar, 12.Pisoni R. Ruggenenti P. Sangalli F. et al.Effect of high dose ramipril with or without indomethacin on glomerular selectivity.Kidney Int. 2002; 62: 1010-1019Abstract Full Text Full Text PDF PubMed Scopus (24) Google Scholar studies have reported evidence that these beneficial effects of angiotensin I-converting enzyme inhibitors and Ang II receptor blockers are indeed dose responsive. We have shown recently13.Fujihara C.K. Velho M. Malheiros D.M.A.C. et al.An extremely high dose of losartan affords superior renoprotection in the remnant model.Kidney Int. 2005; 67: 1913-1924Abstract Full Text Full Text PDF PubMed Scopus (75) Google Scholar that an extremely high dose (500 mg/kg) of the Ang II receptor blocker, losartan potassium (L), can afford more effective preservation of renal structure than a ‘conventional’ dose (50 mg/kg) in rats with 5/6ths renal ablation (Nx). However, whether such unusually high doses would provide similar protection in rats with diabetic nephropathy has not been investigated. The present study was performed nearly 1 year after induction of diabetes mellitus with streptozotocin (STZ) to allow enough time for ‘advanced’ glomerular injury to develop and to investigate: (1) whether either ‘advanced’ or ‘moderate’ lesions can regress on treatment with L and (2) whether stabilization or regression of glomerular injury with L follows a dose–response relationship. The most relevant baseline characteristics, observed at 10 months of DM in groups C, DMUNT, DML50, and DML500, along with those obtained in group DMPRE (pretreatment reference), are given in Table 1. As expected, body weight was reduced, whereas blood glucose (BG) concentration was elevated in the diabetic groups, compared with nondiabetic controls. Tail-cuff pressure (TCP) was similar among groups at this time. As described under section Materials and Methods, the diabetic groups were assembled in such a way that no significant difference among them was observed at this time regarding urinary albumin excretion rate (UalbV), which was markedly elevated relative to C. Likewise, no significant difference among DM groups was noted regarding TCP or BG.Table 1Baseline characteristics of groups DMPRE, DMUNT, DML50, and DML500 immediately before the start of treatments (at 10 months of DM)BW (g)TCP (mm Hg)BG (mg/100 ml)UalbV (mg/day)C (n=12)417±10135±292±424±3DMPRE (n=10)342±8aP<0.05 versus C.134±2405±16aP<0.05 versus C.112±16aP<0.05 versus C.DMUNT (n=8)347±8aP<0.05 versus C.130±2360±18aP<0.05 versus C.114±22aP<0.05 versus C.DML50 (n=11)346±5aP<0.05 versus C.135±1370±15aP<0.05 versus C.111±17aP<0.05 versus C.DML500 (n=12)357±3aP<0.05 versus C.135±2420±17aP<0.05 versus C.113±19aP<0.05 versus C.BG, blood glucose concentration; BW, body weight; TCP, tail-cuff pressure; UalbV, urine albumin excretion rate.a P<0.05 versus C. Open table in a new tab BG, blood glucose concentration; BW, body weight; TCP, tail-cuff pressure; UalbV, urine albumin excretion rate. Figure 1 depicts the time course of BG, TCP, and UalbV along the entire study. There was no difference among diabetic groups regarding these parameters before the initiation of treatments at 10 months of DM. At the end of the treatment period, BG remained similarly elevated in the diabetic groups compared with C (Figure 1a). There was a moderate fall in TCP in both losartan-treated groups (120±4 mm Hg in group DML50 and 115±4 in group DML500, P<0.05 versus C). No significant difference in TCP was observed between groups DML50 and DML500 at the end of treatment (Figure 1b). UalbV rose steadily compared with C in all diabetic groups until 10 months of DM, when treatments were started (Figure 1c). During the treatment period, UalbV remained markedly elevated in untreated rats (group DMUNT), whereas albuminuria regressed to values undistinguishable from control with both Losartan doses (Figure 1c). The fractional mesangial area was significantly increased in the DMPRE group compared with controls (16.9±1.0 versus 10.3±0.9 in C, P<0.05) (Figure 2a and c), and increased further in the DMUNT group, now reaching values more than twice as high as in C, and significantly higher than in the pretreatment group (21.8±1.4, P<0.05 versus C and DMPRE). The fractional mesangial area was significantly lower in groups DML50 and DML500 than in group DMPRE (12.5±0.7 and 12.7±1.2, respectively, P<0.05 versus DMPRE), indicating that Losartan treatment promoted regression of mesangial expansion. No significant difference between the beneficial effects of the two Losartan doses employed was observed. The extent of segmental GS, estimated by the glomerulosclerosis index (GSI), was markedly increased (Figure 2b and d) in the DMPRE group (24.4±3.0 versus 7.9±0.6 in C, P<0.05). The GSI was further augmented in group DMunt (50.5±7.1, P<0.05 versus C and DMPre). As with the fractional mesangial area, GSI dropped below pretreatment values with both losartan doses (11.3±1.4 in DML50 and 14.1±2.4 in DML500, P<0.05 versus DMPRE). Again, no difference was noted between groups DML50 and DML500. When segmental GS (Figure 2b and e) was evaluated by the frequency of sclerotic lesions (percentage of glomerulosclerosis, %GS), a sharp increase above control was observed in group DMPRE (7.1±1.4 versus 1.7±0.4 in C, P<0.05), with a marked additional elevation in group DMUNT (20.9±3.8, P<0.05 versus C and DMPRE). In groups DML50 and DML500, the %GS was significantly lower than in group DMUNT (6.0±2.0 and 7.1±1.6, respectively, P 0.05). Losartan treatment exerted no significant effect on %INT (1.2±0.4 in DML50 and 1.5±0.3 in DML500, P>0.05 versus DMUNT). Data obtained by immunohistochemical detection of macrophages are shown in Figure 3. The number of macrophages detected in glomeruli and at the cortical interstitium was similar to control in group DMPRE, but was significantly increased at both locations in untreated DM rats observed 12 months after STZ injection (group DMUNT). Glomerular macrophage infiltration was prevented by treatment with either dose of Losartan. Likewise, both drug regimens prevented macrophage infiltration at the renal interstitial area, although only in the group treated with the high dose of Losartan was the number of interstitial macrophages significantly lower than in untreated DMUNT rats. No significant difference was found among groups at the end of the study regarding plasma creatinine or potassium concentration. Plasma aldosterone concentration was not significantly different from control in group DMPRE (659±120 pg/ml versus 489±75 in C, P>0.05), but was significantly elevated in group DMUNT (971±141 pg/ml, P<0.05 versus C). Losartan treatment reduced plasma aldosterone concentration to levels not significantly different from those observed in C or DMPRE (508±81 pg/ml in DML50 and 524±85 in DML500, P<0.05 versus DMUNT). In consistency with previous observations,14.Zatz R. Dunn B.R. Meyer T.W. et al.Prevention of diabetic glomerulopathy by pharmacological amelioration of glomerular capillary hypertension.J Clin Invest. 1986; 77: 1925-1930Crossref PubMed Scopus (1069) Google Scholar, 15.Fujihara C.K. Padilha R.M. Zatz R. Glomerular abnormalities in long-term experimental diabetes. Role of hemodynamic and nonhemodynamic factors and effects of antihypertensive therapy.Diabetes. 1992; 41: 286-293Crossref PubMed Scopus (34) Google Scholar, 16.Utimura R. Fujihara C.K. Mattar A.L. et al.Mycophenolate mofetil prevents the development of glomerular injury in experimental diabetes.Kidney Int. 2003; 63: 209-216Abstract Full Text Full Text PDF PubMed Scopus (171) Google Scholar diabetic rats exhibited progressive albuminuria that reached, after 10 months of DM, values more than fivefold higher than in age-matched controls, and 100 times higher than in young controls. The presence of glomerular injury was evident in DM rats 10 months after STZ injection. The most frequent modality of lesion in these rats was diffuse mesangial expansion, as indicated by a marked increase in the mean fractional mesangial area compared with nondiabetic controls. Sclerotic lesions associated with synechiae with Bowman's capsule were observed in about 5% of the glomeruli at this time point. Accordingly, the GSI was threefold higher in these rats than in nondiabetic controls. However, it must be noted that, in consistency with previous findings15.Fujihara C.K. Padilha R.M. Zatz R. Glomerular abnormalities in long-term experimental diabetes. Role of hemodynamic and nonhemodynamic factors and effects of antihypertensive therapy.Diabetes. 1992; 41: 286-293Crossref PubMed Scopus (34) Google Scholar, 16.Utimura R. Fujihara C.K. Mattar A.L. et al.Mycophenolate mofetil prevents the development of glomerular injury in experimental diabetes.Kidney Int. 2003; 63: 209-216Abstract Full Text Full Text PDF PubMed Scopus (171) Google Scholar, 17.Furuta T. Saito T. Ootaka T. et al.The role of macrophages in diabetic glomerulosclerosis.Am J Kidney Dis. 1993; 21: 480-485Abstract Full Text PDF PubMed Scopus (263) Google Scholar diabetic rats exhibited little or no interstitial expansion or inflammation, indicating that renal injury was essentially confined to the glomeruli at this phase. The progressive nature of the nephropathy is stressed by the substantial worsening of glomerular injury observed in untreated DM rats at 12 months, compared with that seen at 10 months, after diabetes induction. Glomerular macrophage infiltration, mesangial expansion and GS were clearly exacerbated at this time, although elevation of serum creatinine was not observed. Likewise, macrophage infiltration of the interstitial area was now evident, in all likelihood heralding the imminent development of interstitial expansion/inflammation. Accordingly, the percent interstitial area was numerically, although not significantly, increased in this group. Of note, the circulating levels of aldosterone were elevated in untreated DM rats, although no sign of extracellular volume depletion was ever seen in these animals. Given the available evidence that aldosterone exerts a profibrotic action in CKD18.Greene E.L. Kren S. Hostetter T.H. Role of aldosterone in the remnant kidney model in the rat.J Clin Invest. 1996; 98: 1063-1068Crossref PubMed Scopus (390) Google Scholar, 19.Schjoedt K.J. Rossing K. Juhl T.R. et al.Beneficial impact of spironolactone in diabetic nephropathy.Kidney Int. 2005; 68: 2829-2836Abstract Full Text Full Text PDF PubMed Scopus (180) Google Scholar, the finding of hyperaldosteronism in group DMUNT is consistent with the view that incipient renal fibrosis may already be developing in these animals at 10 months of DM. Irrespective of dose, Losartan treatment started 10 months after STZ injection sharply reduced albuminuria, which regressed to levels not significantly different compared with nondiabetic controls, indicating restoration of the glomerular barrier properties. The exact mechanisms of this beneficial effect are unclear. It is well established that suppressors of the RAS markedly lower glomerular pressure,14.Zatz R. Dunn B.R. Meyer T.W. et al.Prevention of diabetic glomerulopathy by pharmacological amelioration of glomerular capillary hypertension.J Clin Invest. 1986; 77: 1925-1930Crossref PubMed Scopus (1069) Google Scholar, 15.Fujihara C.K. Padilha R.M. Zatz R. Glomerular abnormalities in long-term experimental diabetes. Role of hemodynamic and nonhemodynamic factors and effects of antihypertensive therapy.Diabetes. 1992; 41: 286-293Crossref PubMed Scopus (34) Google Scholar, 20.Anderson S. Rennke H.G. Garcia D.L. et al.Short and long term effects of antihypertensive therapy in the diabetic rat.Kidney Int. 1989; 36: 526-536Abstract Full Text PDF PubMed Scopus (307) Google Scholar thus lessening the mechanical stress directly imposed on podocytes. Moreover, losartan may have more direct effects on podocytes, which are known to express the AT1 receptor, particularly when exposed to high glucose concentrations,21.Yoo T.H. Li J.J. Kim J.J. et al.Activation of the renin–angiotensin system within podocytes in diabetes.Kidney Int. 2007; 71: 1019-1027Abstract Full Text Full Text PDF PubMed Scopus (92) Google Scholar and to generate Ang II under stretching.22.Durvasula R.V. Petermann A.T. Hiromura K. et al.Activation of a local tissue angiotensin system in podocytes by mechanical strain.Kidney Int. 2004; 65: 30-39Abstract Full Text Full Text PDF PubMed Scopus (265) Google Scholar Losartan treatment may have provided additional renoprotection by abrogating the multiple proinflammatory consequences of AT1 activation.23.Mezzano S. Droguett A. Burgos M.E. et al.Renin–angiotensin system activation and interstitial inflammation in human diabetic nephropathy.Kidney Int Suppl. 2003; 86: S64-S70Abstract Full Text Full Text PDF PubMed Scopus (153) Google Scholar, 24.Vaziri N.D. Bai Y. Ni Z. et al.Intra-renal angiotensin II/AT1 receptor, oxidative stress, inflammation, and progressive injury in renal mass reduction.J Pharmacol Exp Ther. 2007; 323: 85-93Crossref PubMed Scopus (123) Google Scholar Losartan therapy promoted a clear regression of mesangial expansion compared with pretreatment values. These findings are in agreement with previous observations made in diabetic patients, as well as in diabetic and nondiabetic experimental nephropathy,1.Adamczak M. Gross M.L. Krtil J. et al.Reversal of glomerulosclerosis after high-dose enalapril treatment in subtotally nephrectomized rats.J Am Soc Nephrol. 2003; 14: 2833-2842Crossref PubMed Scopus (145) Google Scholar, 3.Fioretto P. Steffes M.W. Sutherland D.E. et al.Reversal of lesions of diabetic nephropathy after pancreas transplantation.N Engl J Med. 1998; 339: 69-75Crossref PubMed Scopus (953) Google Scholar, 4.Ma L.J. Nakamura S. Aldigier J.C. et al.Regression of glomerulosclerosis with high-dose angiotensin inhibition is linked to decreased plasminogen activator inhibitor-1.J Am Soc Nephrol. 2005; 16: 966-976Crossref PubMed Scopus (126) Google Scholar, 5.Remuzzi A. Gagliardini E. Donadoni C. et al.Effect of angiotensin II antagonism on the regression of kidney disease in the rat.Kidney Int. 2002; 62: 885-894Abstract Full Text Full Text PDF PubMed Scopus (75) Google Scholar, 6.Takahashi H. Ichihara A. Kaneshiro Y. et al.Regression of nephropathy developed in diabetes by (Pro)renin receptor blockade.J Am Soc Nephrol. 2007; 18: 2054-2061Crossref PubMed Scopus (119) Google Scholar, 25.Marinides G.N. Groggel G.C. Cohen A.H. et al.Enalapril and low protein reverse chronic puromycin aminonucleoside nephropathy.Kidney Int. 1990; 37: 749-757Abstract Full Text PDF PubMed Scopus (67) Google Scholar, 26.Ikoma M. Kawamura T. Kakinuma Y. et al.Cause of variable therapeutic efficiency of angiotensin converting enzyme inhibitor on glomerular lesions.Kidney Int. 1991; 40: 195-202Abstract Full Text PDF PubMed Scopus (140) Google Scholar and indicate that the mesangial enlargement observed in association with the STZ-induced diabetes model is a readily reversible process. The mechanisms underlying the regression of mesangial expansion by losartan treatment are yet to be determined. Losartan treatment can arrest the abnormal synthesis of mesangial matrix by attenuating or abolishing glomerular hypertension and its local inflammatory consequences, such as activation of the RAS,27.Becker B.N. Yasuda T. Kondo S. et al.Mechanical stretch/relaxation stimulates a cellular renin–angiotensin system in cultured rat mesangial cells.Exp Nephrol. 1998; 6: 57-66Crossref PubMed Scopus (54) Google Scholar enhanced proliferation of mesangial cells28.Harris R.C. Haralson M.A. Badr K.F. Continuous stretch-relaxation in culture alters rat mesangial cell morphology, growth characteristics, and metabolic activity.Lab Invest. 1992; 66: 548-554PubMed Google Scholar, 29.Kawata Y. Mizukami Y. Fujii Z. et al.Applied pressure enhances cell proliferation through mitogen-activated protein kinase activation in mesangial cells.J Biol Chem. 1998; 273: 16905-16912Crossref PubMed Scopus (56) Google Scholar, and increased production of transforming growth factor-β30.Riser B.L. Cortes P. Heilig C. et al.Cyclic stretching force selectively up-regulates transforming growth factor-beta isoforms in cultured rat mesangial cells.Am J Pathol. 1996; 148: 1915-1923PubMed Google Scholar and mesangial matrix.31.Riser B.L. Cortes P. Zhao X. et al.Intraglomerular pressure and mesangial stretching stimulate extracellular matrix formation in the rat.J Clin Invest. 1992; 90: 1932-1943Crossref PubMed Scopus (234) Google Scholar In addition, suppression of the RAS has been shown to restore the glomerular expression of matrix metalloproteinases such as MMP-2 and MMP-9 (MMPs), which is depressed in diabetic kidney,32.McLennan S.V. Kelly D.J. Cox A.J. et al.Decreased matrix degradation in diabetic nephropathy: effects of ACE inhibition on the expression and activities of matrix metalloproteinases.Diabetologia. 2002; 45: 268-275Crossref PubMed Scopus (124) Google Scholar and to decrease that of plasminogen activator inhibitor 1 in nondiabetic kidney disease,33.Ma L.J. Nakamura S. Whitsitt J.S. et al.Regression of sclerosis in aging by an angiotensin inhibition-induced decrease in PAI-1.Kidney Int. 2000; 58: 2425-2436Abstract Full Text Full Text PDF PubMed Scopus (124) Google Scholar thus allowing quick degradation of the excess mesangial matrix. Since the early observations on the regression of GS, it has been questioned whether this process can occur even after the tuft architecture has undergone severe distortion.8.Kriz W. LeHir M. Pathways to nephron loss starting from glomerular diseases—insights from animal models.Kidney Int. 2005; 67: 404-419Abstract Full Text Full Text PDF PubMed Scopus (349) Google Scholar, 25.Marinides G.N. Groggel G.C. Cohen A.H. et al.Enalapril and low protein reverse chronic puromycin aminonucleoside nephropathy.Kidney Int. 1990; 37: 749-757Abstract Full Text PDF PubMed Scopus (67) Google Scholar, 26.Ikoma M. Kawamura T. Kakinuma Y. et al.Cause of variable therapeutic efficiency of angiotensin converting enzyme inhibitor on glomerular lesions.Kidney Int. 1991; 40: 195-202Abstract Full Text PDF PubMed Scopus (140) Google Scholar The discussion of this important aspect is often complicated by the lack of a clear-cut distinction between ‘moderate’ and ‘severe’ GS. To obviate this problem, the term ‘GS’ was reserved in the present study to lesions involving not only matrix deposition at the mesangial area but also confluence of deposits, occlusion of capillary loops and, especially, the presence of synechiae of the tuft with Bowman's capsule, used as an exclusion criterion. When the effect of losartan treatment on GS was analyzed using the GSI, the results largely agreed with those obtained for mesangial expansion: the GSI was reduced to levels significantly lower than before treatment, again indicating regression of glomerular injury. However, when results were expressed in terms of the percent of glomeruli showing sclerosing lesions, a different picture emerged: although the %GS was significantly lower in losartan-treated than in untreated diabetic rats, indicating efficient renoprotection, it was similar to that observed before treatment, a finding seemingly inconsistent with regression of GS. This is only an apparent contradiction. ‘True’ GS was invariably associated with exuberant expansion of the mesangial matrix in the vicinity of the synechiae. Since the GSI measures both the frequency and the extent of the sclerotic lesions, its decline on losartan treatment inevitably reflects in part the simultaneous clearance of the excess mesangial matrix. By contrast, the formation of synechiae involves a profound local rearrangement of the glomerular structure, with podocyte effacement and invasion by parietal cells, along with periglomerular inflammation and fibrosis.8.Kriz W. LeHir M. Pathways to nephron loss starting from glomerular diseases—insights from animal models.Kidney Int. 2005; 67: 404-419Abstract Full Text Full Text PDF PubMed Scopus (349) Google Scholar Conceivably, such alterations, as well as more advanced structural injury such as interstitial fibrosis, are less prone to regression than simple mesangial expansion, since the action of degrading enzymes, though efficient to clear even large deposits of matrix components,
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