Turner, Neil

Zhou, Y. S.

English

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     Edinburgh Research Explorer                                      New Ways of Thinking about Proteinuria and Progression ofRenal DamageCitation for published version:Zhou, YS & Turner, N 2010, 'New Ways of Thinking about Proteinuria and Progression of Renal Damage'Nephron. Experimental nephrology, vol 116, no. 1, pp. E1-E2., 10.1159/000314667Digital Object Identifier (DOI):10.1159/000314667Link:Link to publication record in Edinburgh Research ExplorerDocument Version:Publisher final version (usually the publisher pdf)Published In:Nephron. Experimental nephrologyPublisher Rights Statement:Free AccessGeneral rightsCopyright for the publications made accessible via the Edinburgh Research Explorer is retained by the author(s)and / or other copyright owners and it is a condition of accessing these publications that users recognise andabide by the legal requirements associated with these rights.Take down policyThe University of Edinburgh has made every reasonable effort to ensure that Edinburgh Research Explorercontent complies with UK legislation. If you believe that the public display of this file breaches copyright pleasecontact openaccess@ed.ac.uk providing details, and we will remove access to the work immediately andinvestigate your claim.Download date: 20. Feb. 2015Fax +41 61 306 12 34E-Mail karger@karger.chwww.karger.com Editorial  Nephron Exp Nephrol 2010;116:e1–e2  DOI: 10.1159/000314667  New Ways of Thinking about Proteinuria and Progression of Renal Damage  Y.S. Zhou    A.N. Turner  MRC Centre for Inflammation, University of Edinburgh,  Edinburgh , UK  The ‘Podocyte-Progression hypothesis’  [3–5] postu-lates that continuing, progressive podocyte damage or loss is central to the progression of proteinuric renal dis-eases. This mechanism of progression might also be ex-tended to diseases in which podocyte damage is not the primary problem, but in which proteinuria occurs later, possibly in hyperfiltering glomeruli, for example. If we believe this, we might expect nephroprotective, proteinuria-lowering treatments to act not via haemody-namic or anti-fibrotic effects, but on podocytes them-selves. Evidence to support this hypothesis is now strong. It turns out that podocytes are dynamic, active, mobile cells that are studded with scores of receptor types en-abling them to respond to external mediators. The slit diaphragm is not a static barrier to protein; it is suscep-tible to a wide range of external influences both chemical and mechanical. Five years ago came the first suggestion that one of our key immunosuppressive agents, corticosteroids – the mainstay of therapy for minimal change nephrotic syn-drome – might have direct structure-protective effects on podocytes  [6] . That has recently been added to by the ob-servation that the immunosuppressive calcineurin inhib-itor tacrolimus has similar direct effects  [7, 8] . Both of these drugs had previously been assumed to be acting through the immune system, though that fitted poorly with the observation that calcineurin inhibitors seemed to reduce proteinuria regardless of the cause. The evi- Reducing proteinuria is often a target of treatment  because of the close correlation between improvementof proteinuria and better renal outcomes in human stud-ies involving angiotensin-converting enzyme inhibitors (ACEI) and angiotensin receptor blockers (ARB). Conventional explanations for the protective effects of ACEI and ARB centre on their haemodynamic effects, suggesting that reducing glomerular filtration pressure is the key to their protective action. The fact that blood pressure reduction by any means protects renal function in proteinuric renal disease (the Modification of Diet in Renal Disease Study) suggests that this can explain at least some of the effect. Others have added that ACEI/ARB may also modulate the toxicity of filtered proteins by effects on non-glomerular cells  [1] . The close correla-tion between long-term outcomes and proteinuria has triggered a large body of work documenting potential mechanisms by which excessive filtered protein may damage renal tubular cells and promote interstitial fibro-sis  [2] . An alternative hypothesis is emerging from the mush-rooming field of podocyte biology. Podocytes have been show to play a central role in many or most proteinuric diseases – almost all of the inherited causes of severe pro-teinuria involve podocyte genes and many acquired pro-teinuric diseases can point to podocyte malfunction as well. Proteinuria is known to be a consequence of podo-cyte malfunction or damage. Published online: May 21, 2010  Neil Turner  Renal and Autoimmunity Group  MRC Centre for Inflammation, University of Edinburgh  Hugh Robson Building, 14 George Square, Edinburgh EH8 9XD (UK)  Tel. +44 131 651 1795, Fax +44 131 651 1848, E-Mail neil.turner   @   ed.ac.uk  © 2010 S. Karger AG, Basel1660–2129/10/1161–0001$26.00/0  Accessible online at:www.karger.com/nee Downloaded by: University of Edinburgh                                129.215.4.1 - 6/19/2013 1:32:32 AM Zhou/Turner Nephron Exp Nephrol 2010;116:e1–e2e2dence that minimal change nephropathy is an immune-mediated condition now looks seriously weakened. It is fascinating that drugs acting on the immune system can have such effects on podocytes and this must point to shared signalling pathways. It is logical to ask next whether other drugs that appear to reduce proteinuria, or maintain remissions in nephrot-ic syndrome, could have direct actions on podocytes. In this issue, Takeuchi et al.  [9] set out to investigate the im-idazole nucleoside mizoribine, which is an inhibitor of purine nucleotide synthesis that is apparently commonly used as an immunosuppressant in Japan. The chosen model was puromycin aminonucleoside (PAN) nephropathy in rats. PAN is believed to act pri-marily as a podocyte toxin in this model, causing protein-uria and podocyte injury. Mizoribine acted to protect podocytes in vitro against loss of actin structure and cell death induced by puromycin and in the in vivo model, it reduced proteinuria and preserved nephrin distribution pattern at 9 days. Unfortunately, this is the limit of the in vivo data but a protective effect has been described previ-ously by another group. Some observations on potential mechanisms are presented and it is interesting that the investigators found that there was no evidence in theirin vitro system to support a mechanism involving in-hibition of inosine 5  -monophosphate dehydrogenase, thought to be the main immunosuppressive action of the drug. Interestingly or surprisingly, in this same in vitro sys-tem the investigators found no protection from mycophe-nolate mofetil, which is quite extensively used to main-tain remission in minimal change disease. It is only fair to point out that the published random-ized controlled trial evidence for the efficacy of mizorib-ine in nephrotic syndrome is rather limited, and a Co-chrane review  [10] regarded it as inconclusive. However, the evidence for mycophenolate mofetil is not solid either. Further studies of potential actions of nephroprotective drugs on podocytes are to be looked forward to.  References  1 Rosenberg ME, Smith LJ, Correa-Rotter R, Hostetter TH: The paradox of the renin-an-giotensin system in chronic renal disease. Kidney Int 1994; 45: 403–410.  2 Baines RJ, Brunskill NJ: The molecular in-teractions between filtered proteins and proximal tubular cells in proteinuria. Neph-ron Exp Nephrol 2008; 110:e67–e71.  3 Gassler N, Elger M, Kränzlin B, Kriz W, et al: Podocyte injury underlies the progression of focal segmental glomerulosclerosis in the Fa/Fa Zucker rat. Kidney Int 2001; 60: 106–116.  4 Ichikawa I, Ma J, Motojima M, Matsusaka T: Podocyte damage damages podocytes: au-tonomous vicious cycle that drives local spread of glomerular sclerosis. Curr Opin Nephrol Hypertens 2005; 14: 205–210.  5 Wharram BL, Goyal M, Wiggins JE, et al: Podocyte depletion causes glomerulosclero-sis: diphtheria toxin-induced podocyte de-pletion in rats expressing human diphtheria toxin receptor transgene. J Am Soc Nephrol 2005; 16: 2941–2952.  6 Ransom RF, Lam NG, Hallett MA, Atkinson SJ, Smoyer WE: Glucocorticoids protect and enhance recovery of cultured murine podo-cytes via actin filament stabilization. Kidney Int 2005; 68: 2473–2483.  7 Faul C, Donnelly M, Merscher-Gomez S, Chang YH, Franz S, Delfgaauw J, Chang JM, Choi HY, Campbell KN, Kim K, Reiser J, Mundel P: The actin cytoskeleton of kidney podocytes is a direct target of the antipro-teinuric effect of cyclosporine A. Nat Med 2008; 14: 931–938.  8 Mathieson PW: Proteinuria and immunity – an overstated relationship? N Engl J Med 2008; 359: 2492–2494.  9 Takeuchi S, Hiromura K, Tomioka M, et al: The immunosuppressive drug mizoribine directly prevents podocyte injury in puro-mycin aminonucleoside nephrosis. Nephron Exp Nephrol 2010;116:e3–e10.  10 Hodson EM, Willis N, Craig JC: Non-corti-costeroid treatment for nephrotic syndrome in children. Cochrane Database of System-atic Reviews: Reviews 2008, Issue 1. DOI: 10.1002/14651858.CD002290.pub3.  Downloaded by: University of Edinburgh                                129.215.4.1 - 6/19/2013 1:32:32 AM

7 F a u l C , D o n n e l l y M , M e r s c h e r - G o m e z

al: Podocyte depletion causes glomerulosclerosis: diphtheria toxin-induced podocyte depletion in rats expressing human diphtheria toxin receptor transgene.

NJ: The molecular interactions between filtered proteins and proximal tubular cells in proteinuria. Nephron Exp Nephrol

Non-corticosteroid treatment for nephrotic syndrome in children. Cochrane Database of Systematic Reviews: Reviews 2008, Issue 1. DOI: 10.1002/14651858.CD002290.pub3. D o w n l o a d e d b y : U n i v e r s i t y o f E d i n b u r g h .

Podocyte damage damages podocytes: autonomous vicious cycle that drives local sp r ead o f gl o m erular scl erosis. Curr Op in Nephrol Hypertens

Podocyte injury underlies the progression of focal segmental glomerulosclerosis in the Fa/Fa Zucker rat. Kidney Int

PW: Proteinuria and immunity – an overstated relationship?

Smoyer WE: Glucocorticoids protect and enhance recovery of cultured murine podocytes via actin filament stabilization. Kidney Int

The immunosuppressive drug mizoribine directly prevents podocyte injury in puromycin aminonucleoside nephrosis. Nephron Exp Nephrol 2010;116:e3–e10.

New Ways of Thinking about Proteinuria and Progression of Renal Damage

     Edinburgh Research Explorer                                      New Ways of Thinking about Proteinuria and Progression ofRenal DamageCitation for published version:Zhou, YS & Turner, N 2010, 'New Ways of Thinking about Proteinuria and Progression of Renal Damage',Nephron Experimental Nephrology, vol. 116, no. 1, pp. E1-E2. https://doi.org/10.1159/000314667Digital Object Identifier (DOI):10.1159/000314667Link:Link to publication record in Edinburgh Research ExplorerDocument Version:Publisher's PDF, also known as Version of recordPublished In:Nephron Experimental NephrologyPublisher Rights Statement:Free AccessGeneral rightsCopyright for the publications made accessible via the Edinburgh Research Explorer is retained by the author(s)and / or other copyright owners and it is a condition of accessing these publications that users recognise andabide by the legal requirements associated with these rights.Take down policyThe University of Edinburgh has made every reasonable effort to ensure that Edinburgh Research Explorercontent complies with UK legislation. If you believe that the public display of this file breaches copyright pleasecontact openaccess@ed.ac.uk providing details, and we will remove access to the work immediately andinvestigate your claim.Download date: 28. Nov. 2025Fax +41 61 306 12 34E-Mail karger@karger.chwww.karger.com Editorial  Nephron Exp Nephrol 2010;116:e1–e2  DOI: 10.1159/000314667  New Ways of Thinking about Proteinuria and Progression of Renal Damage  Y.S. Zhou    A.N. Turner  MRC Centre for Inflammation, University of Edinburgh,  Edinburgh , UK  The ‘Podocyte-Progression hypothesis’  [3–5] postu-lates that continuing, progressive podocyte damage or loss is central to the progression of proteinuric renal dis-eases. This mechanism of progression might also be ex-tended to diseases in which podocyte damage is not the primary problem, but in which proteinuria occurs later, possibly in hyperfiltering glomeruli, for example. If we believe this, we might expect nephroprotective, proteinuria-lowering treatments to act not via haemody-namic or anti-fibrotic effects, but on podocytes them-selves. Evidence to support this hypothesis is now strong. It turns out that podocytes are dynamic, active, mobile cells that are studded with scores of receptor types en-abling them to respond to external mediators. The slit diaphragm is not a static barrier to protein; it is suscep-tible to a wide range of external influences both chemical and mechanical. Five years ago came the first suggestion that one of our key immunosuppressive agents, corticosteroids – the mainstay of therapy for minimal change nephrotic syn-drome – might have direct structure-protective effects on podocytes  [6] . That has recently been added to by the ob-servation that the immunosuppressive calcineurin inhib-itor tacrolimus has similar direct effects  [7, 8] . Both of these drugs had previously been assumed to be acting through the immune system, though that fitted poorly with the observation that calcineurin inhibitors seemed to reduce proteinuria regardless of the cause. The evi- Reducing proteinuria is often a target of treatment  because of the close correlation between improvementof proteinuria and better renal outcomes in human stud-ies involving angiotensin-converting enzyme inhibitors (ACEI) and angiotensin receptor blockers (ARB). Conventional explanations for the protective effects of ACEI and ARB centre on their haemodynamic effects, suggesting that reducing glomerular filtration pressure is the key to their protective action. The fact that blood pressure reduction by any means protects renal function in proteinuric renal disease (the Modification of Diet in Renal Disease Study) suggests that this can explain at least some of the effect. Others have added that ACEI/ARB may also modulate the toxicity of filtered proteins by effects on non-glomerular cells  [1] . The close correla-tion between long-term outcomes and proteinuria has triggered a large body of work documenting potential mechanisms by which excessive filtered protein may damage renal tubular cells and promote interstitial fibro-sis  [2] . An alternative hypothesis is emerging from the mush-rooming field of podocyte biology. Podocytes have been show to play a central role in many or most proteinuric diseases – almost all of the inherited causes of severe pro-teinuria involve podocyte genes and many acquired pro-teinuric diseases can point to podocyte malfunction as well. Proteinuria is known to be a consequence of podo-cyte malfunction or damage. Published online: May 21, 2010  Neil Turner  Renal and Autoimmunity Group  MRC Centre for Inflammation, University of Edinburgh  Hugh Robson Building, 14 George Square, Edinburgh EH8 9XD (UK)  Tel. +44 131 651 1795, Fax +44 131 651 1848, E-Mail neil.turner   @   ed.ac.uk  © 2010 S. Karger AG, Basel1660–2129/10/1161–0001$26.00/0  Accessible online at:www.karger.com/nee Downloaded by: University of Edinburgh                                129.215.4.1 - 6/19/2013 1:32:32 AM Zhou/Turner Nephron Exp Nephrol 2010;116:e1–e2e2dence that minimal change nephropathy is an immune-mediated condition now looks seriously weakened. It is fascinating that drugs acting on the immune system can have such effects on podocytes and this must point to shared signalling pathways. It is logical to ask next whether other drugs that appear to reduce proteinuria, or maintain remissions in nephrot-ic syndrome, could have direct actions on podocytes. In this issue, Takeuchi et al.  [9] set out to investigate the im-idazole nucleoside mizoribine, which is an inhibitor of purine nucleotide synthesis that is apparently commonly used as an immunosuppressant in Japan. The chosen model was puromycin aminonucleoside (PAN) nephropathy in rats. PAN is believed to act pri-marily as a podocyte toxin in this model, causing protein-uria and podocyte injury. Mizoribine acted to protect podocytes in vitro against loss of actin structure and cell death induced by puromycin and in the in vivo model, it reduced proteinuria and preserved nephrin distribution pattern at 9 days. Unfortunately, this is the limit of the in vivo data but a protective effect has been described previ-ously by another group. Some observations on potential mechanisms are presented and it is interesting that the investigators found that there was no evidence in theirin vitro system to support a mechanism involving in-hibition of inosine 5  -monophosphate dehydrogenase, thought to be the main immunosuppressive action of the drug. Interestingly or surprisingly, in this same in vitro sys-tem the investigators found no protection from mycophe-nolate mofetil, which is quite extensively used to main-tain remission in minimal change disease. It is only fair to point out that the published random-ized controlled trial evidence for the efficacy of mizorib-ine in nephrotic syndrome is rather limited, and a Co-chrane review  [10] regarded it as inconclusive. However, the evidence for mycophenolate mofetil is not solid either. Further studies of potential actions of nephroprotective drugs on podocytes are to be looked forward to.  References  1 Rosenberg ME, Smith LJ, Correa-Rotter R, Hostetter TH: The paradox of the renin-an-giotensin system in chronic renal disease. Kidney Int 1994; 45: 403–410.  2 Baines RJ, Brunskill NJ: The molecular in-teractions between filtered proteins and proximal tubular cells in proteinuria. Neph-ron Exp Nephrol 2008; 110:e67–e71.  3 Gassler N, Elger M, Kränzlin B, Kriz W, et al: Podocyte injury underlies the progression of focal segmental glomerulosclerosis in the Fa/Fa Zucker rat. Kidney Int 2001; 60: 106–116.  4 Ichikawa I, Ma J, Motojima M, Matsusaka T: Podocyte damage damages podocytes: au-tonomous vicious cycle that drives local spread of glomerular sclerosis. Curr Opin Nephrol Hypertens 2005; 14: 205–210.  5 Wharram BL, Goyal M, Wiggins JE, et al: Podocyte depletion causes glomerulosclero-sis: diphtheria toxin-induced podocyte de-pletion in rats expressing human diphtheria toxin receptor transgene. J Am Soc Nephrol 2005; 16: 2941–2952.  6 Ransom RF, Lam NG, Hallett MA, Atkinson SJ, Smoyer WE: Glucocorticoids protect and enhance recovery of cultured murine podo-cytes via actin filament stabilization. Kidney Int 2005; 68: 2473–2483.  7 Faul C, Donnelly M, Merscher-Gomez S, Chang YH, Franz S, Delfgaauw J, Chang JM, Choi HY, Campbell KN, Kim K, Reiser J, Mundel P: The actin cytoskeleton of kidney podocytes is a direct target of the antipro-teinuric effect of cyclosporine A. Nat Med 2008; 14: 931–938.  8 Mathieson PW: Proteinuria and immunity – an overstated relationship? N Engl J Med 2008; 359: 2492–2494.  9 Takeuchi S, Hiromura K, Tomioka M, et al: The immunosuppressive drug mizoribine directly prevents podocyte injury in puro-mycin aminonucleoside nephrosis. Nephron Exp Nephrol 2010;116:e3–e10.  10 Hodson EM, Willis N, Craig JC: Non-corti-costeroid treatment for nephrotic syndrome in children. Cochrane Database of System-atic Reviews: Reviews 2008, Issue 1. DOI: 10.1002/14651858.CD002290.pub3.  Downloaded by: University of Edinburgh                                129.215.4.1 - 6/19/2013 1:32:32 AM

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New Ways of Thinking about Proteinuria and Progression of Renal Damage

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