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Chronic kidney disease (CKD) is a major cause of morbidity and mortality, resulting in progressive scarring of renal parenchyma and culminating in the development of end-stage renal disease. In many other parenchymal diseases, such as left ventricular hypertrophy and atherosclerosis of coronary arteries, scarring can be at least partially reversed to restore more normal tissue structure and function. In humans, however, no new glomeruli can be generated after term birth. The apparent inexorable progression of renal scarring characteristic of CKD is postulated to start with disease-specific injury, which then acti-vates compensatory but ultimately mal adaptive changes, such as hemodynamic alterations and altered growth responses, in the remaining nephrons. Nevertheless, even advanced sclerotic glomeruli are not inert, but have ongoing cell turnover and, therefore, there is potential for modulation of these processes.

Recent data from both animals and humans have documented the potential reversibility and mechanisms of glomerulosclerosis, and examined mechanisms of glomerular remodel ing.1 Interest has focused on angiotensin-converting-enzyme inhibitors (ACEIs), because of their efficacy in lowering glomerular pressure even beyond systemic pressures, by decreasing efferent arteriolar resistance. Early studies in the / nephrectomy model, using delayed inter vention starting at a point of established sclerosis, indicated that higher doses of ACEIs were more effective than normal antihypertensive doses in ameliorating development of glomerulo sclerosis, despite having similar efficacy in normalizing systemic and glomerular blood pressures.1 In some rats, the extent and severity of sclerosis after this intervention was even less at autopsy than at biopsy 4 weeks earlier, indicating regression of glomerulosclerosis.1 More recent studies by the groups of Ritz, Remuzzi, Zatz, Chatziantoniou, and myself, have explored the mechanisms and potential for regression of glomerulosclerosis in rodent models.2–7 Ritz and co-workers sacrificed subgroups of rats at different times after subtotal

Can glomerulosclerosis be reversed?Agnes B Fogo

AB Fogo is Professor of Pathology, Medicine and Pediatrics and Director of the Renal/Electron Microscopy Laboratory at Vanderbilt University Medical Center, Nashville, TN, USA.

CorrespondenceMCN C3310Department of PathologyVanderbilt University Medical CenterNashvilleTN 37232USAagnes.fogo@vanderbilt.edu

Received 5 September 2005Accepted 24 January 2006

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nephrectomy and showed that a 4-week course of high-dose enala pril initiated 8 weeks after the initial injury decreased glomerulosclerosis, vascular lesions and tubulointerstitial fibrosis to levels lower than those seen at the start of treat-ment. In these studies, the number of podo-cytes per glomerulus was not changed by ACEI treatment, but the volume of the podocytes was increased. By contrast, mesangial and endo thelial cell prolifera tion was reversed by an ACEI, with a corresponding reduction in glomerular volume and capillary number.3 In our recent prelimi-nary studies in a different variant of the remnant kidney model, we have observed simplification of capillary branching in untreated sclerotic rats, with increased capillary branching occur-ring when ACEIs were used to induce regres-sion of sclerosis. This observation indicates that increased capillary growth can take place when regression is induced.

Although regression of sclerosis was achieved in the above studies using angiotensin inhibition, regression did not occur in all animals, and the kidney structure was not completely normalized, suggesting that additional mechanisms promoting sclerosis were still active. Indeed, elegant studies from Remuzzi’s group support the idea that combination therapy with an ACEI, angiotensin receptor blocker (ARB) and statin can achieve better results on sclerosis than monotherapy with any one of these classes of drug.4 The dose used is also important: it appears that super-high doses of either ACEIs or ARBs are necessary to achieve regression. Although glomerular pressure was lowered to a similar extent by an extremely high dose and a lower dose of the ARB losartan, the higher dose had additional beneficial effects not seen with the lower dose, decreasing renal inflamma tion and restoring glomerular and interstitial injury to pretreatment levels.

Multiple profibrotic mechanisms are activated in models of progressive sclerosis, and the mani-fold effects of angiotensin modulate many of these processes. Matrix accumulation is modulated by proteases and their inhibitors, such as the matrix

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VIEWPOINT

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GLOSSARY5/6 NEPHRECTOMY MODEL A widely used experimental model of chronic renal failure in which five-sixths of the kidney is ablated

Competing interestsThe author declared she has no competing interests.

metalloproteases (MMPs) and tissue inhibitors of matrix metalloproteases (TIMPs), and by factors that promote matrix synthesis, including transforming growth factor β1 (TGF-β1). In our studies of regression in the remnant kidney model, high-dose angiotensin inhibition neither increased MMP messenger RNA or activity, nor reduced TGF-β1 messenger RNA,7 indicating that such effects could not account for the observed regression, in contrast to observations in other settings.4,6 Regression of sclerosis induced by ACEI treatment was, however, tightly linked to decreases in plasminogen activator inhibitor 1 (PAI-1) and TIMP-1 in our studies.8 Angiotensin can directly induce PAI-1, a molecule that promotes fibrosis by both plasmin-dependent and plasmin-independent mechanisms. Of interest, inhibition of aldosterone by spirono lactone decreased PAI-1 levels and induced regression of sclerosis in some animals.8

What then are the limits for the potential of regression? Mathematical modeling has indi-cated that individual glomerular tufts with sclerosis occupying >50% of the capillaries are doomed to progression.1 Conversely, glomeruli with <50% sclerosis of the tuft are capable of growing new capillary loops. Elegant morpho-metric studies by Nyengaard of CKD in children and rats have demonstrated that both lengthening and branching of glomerular capillaries occurs after injury.1 Proof of principle of regression has also been shown in human diabetic nephropathy by Fioretto et al.,1 where cure of the underlying diabetes by pancreas transplantation resulted in regression of the existing sclerotic renal lesions and tubulointerstitial fibrosis over a 10-year follow-up period, as verified by repeat biopsies.

The complex interactions of cells within the glomerulus clearly affect the potential for regression of sclerosis. Although mesangial cells readily proliferate and can be replenished after injury, the interaction between podocytes and endo thelium is quite complex. The podo-cyte normally secretes specific growth factors, including vascular endothelial growth factor-A (VEGF-A) and angio poietin-1, which are key for maintaining normal glomerular endo-thelial function and fenestration. Glomerular VEGF and capillary density were decreased in the rat remnant kidney model of glomerulo-sclerosis and, conversely, treatment with VEGF ameliorated development of glomerulo sclerosis

and tubulointerstitial fibrosis.9 Our recent studies indicate that angiotensin inhibition, in addition to effects on blood pressure, extra-cellular matrix and other growth factors, might also influence modulation of glomerular endo-thelial cell growth by podocytes. Our results show that medium from injured podocytes was in effective in stimulating endothelial cell sprouting and growth, as a result of reduced VEGF-A and angiopoietin-1. These endo thelial cell responses could be restored by treatment of the injured podocytes with an ARB. Furthermore, the responses were blocked by antibodies inhibit ing these angiogenic proteins. These data imply that angiotensin inhibition could contribute to regression by altering podocyte modulation of capillary remodeling.10

In summary, current experimental and human data support the idea that there is potential for regression of existing glomerulosclerosis, especially with multipronged interventions. Angiotensin appears to be a key mediator of many of the processes involved in glomerulosclerosis, affecting blood pressure, extracellular matrix and the interaction of podocytes with capillaries.

References1 Fogo A (2001) Progression and potential regression of

glomerulosclerosis. Kidney Int 59: 804–8192 Adamczak M et al. (2003) Reversal of

glomerulosclerosis after high-dose enalapril treatment in subtotally nephrectomized rats. J Am Soc Nephrol 14: 2833–2842

3 Adamczak M et al. (2004) Reversal of glomerular lesions involves coordinated restructuring of glomerular microvasculature. J Am Soc Nephrol 15: 3063–3072

4 Zoja C et al. (2002) How to fully protect the kidney in a severe model of progressive nephropathy: a multidrug approach. J Am Soc Nephrol 13: 2898–2908

5 Fujihara CK et al. (2005) An extremely high dose of losartan affords superior renoprotection in the remnant model. Kidney Int 67: 1913–1924

6 Boffa JJ et al. (2003) Regression of renal vascular and glomerular fibrosis: role of angiotensin II receptor antagonism and matrix metalloproteinases. J Am Soc Nephrol 14: 1132–1144

7 Ma LJ et al. (2005) Regression of glomerulosclerosis with high-dose angiotensin inhibition is linked to decreased plasminogen activator inhibitor-1. J Am Soc Nephrol 16: 966–976

8 Aldigier JC et al. (2005) Regression of existing glomerulosclerosis by inhibition of aldosterone. J Am Soc Nephrol 16: 3306–3314

9 Kang DH et al. (2001) Impaired angiogenesis in the remnant kidney model: II. Vascular endothelial growth factor administration reduces renal fibrosis and stabilizes renal function. J Am Soc Nephrol 12: 1448–1457

10 Liang X et al. Angiotensin type 1 receptor blocker restores podocyte potential to promote glomerular endothelial outgrowth. J Am Soc Nephrol, in press

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