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• W2019912184 abstract "In blood there are a number of inflammatory mediators that can be instantly activated, and these must be kept under tight constraint to prevent their inadvertent activation. An example of such a system is that of complement, which consists of more than 30 proteins. Specialized plasma membrane proteins are present on cells exposed to blood to limit complement activation. For instance, the regulators of complement activation proteins, complement receptor 1 (CR1), decay accelerating factor and membrane cofactor protein are widely expressed. In rodents, a genetic and functional homologue to these proteins is Crry, which is an abbreviation for CR1-related gene/protein y. Under normal circumstances, the glomerulus does a remarkable job of restricting plasma proteins from entering the 170 liters of daily glomerular ultrafiltrate. Hence, the apical portions of tubular cells are exposed to a largely protein-free solution. In the case of the complement cascade, the large sizes of nearly all of the member proteins further restrict their passage into urine. As such, it is not crucial to protect against complement activation in the portions of tubular cells that are exposed to urine. Appropriately, the expression of complement regulators is low in the apical regions of tubular cells in both human and rodent kidney1Funabashi K. Okada N. Matsuo S. Yamamoto T. Morgan B.P. Okada H. Tissue distribution of complement regulatory membrane proteins in rats.Immunology. 1994; 81: 444-451PubMed Google Scholar,2Ichida S. Yuzawa Y. Okada H. Yoshioka K. Matsuo S. Localization of the complement regulatory proteins in the normal human kidney.Kidney Int. 1994; 46: 89-96Abstract Full Text PDF PubMed Scopus (134) Google Scholar. In conditions in which the glomerular permselectivity barrier is impaired, plasma proteins appear in the urinary space. Progressive glomerular diseases are invariably accompanied by tubulointerstitial damage, the extent of which is closely linked to an adverse renal outcome. It has been postulated that individual proteins such as albumin, transferrin and lipoproteins can directly or indirectly lead to tubulointerstitial injury3Nath K.A. Tubulointerstitial changes as a major determinant in the progression of renal damage.Am J Kidney Dis. 1992; 20: 1-17Abstract Full Text PDF PubMed Scopus (805) Google Scholar,4Eddy A.A. Experimental insights into the tubulointerstitial disease accompanying primary glomerular disease.J Am Soc Nephrol. 1994; 5: 1273-1287Crossref PubMed Google Scholar. The various proteins of the complement system are among the proteins appearing in urine in nonselective glomerular proteinuria, and their activation has also been suggested to contribute to this tubulointerstitial damage5Biancone L. David S. Della Pietra V. Montrucchio G. Cambi V. Camussi G. Alternative pathway activation of complement by cultured human proximal tubular epithelial cells.Kidney Int. 1994; 45: 451-460Abstract Full Text PDF PubMed Scopus (115) Google Scholar. In this issue of Kidney International, Hori et al produced glomerular proteinuria by injecting rats with the glomerular epithelial cell toxin, puromycin aminonucleoside6Hori Y. Yamada K. Hanafusa N. Okuda T. Okada N. Miyata T. Couser W.G. Kurokawa K. Fujita T. Nangaku M. Crry, a complement regulatory protein, modulates renal interstitial disease induced by proteinuria.Kidney Int. 1999; 56: 2096-2106Abstract Full Text Full Text PDF PubMed Scopus (47) Google Scholar. Over the course of this study, animals developed morphological evidence of tubulointerstitial damage. The documented deposition of C3 and C5b-9 on tubular cells was circumstantial evidence that complement activation was pathogenic. However, animals in which antisense oligonucleotides were used to effectively eliminate what Crry was available to limit against complement activation had significantly greater complement deposition and tubular injury. These findings show that intrinsic complement regulation (by Crry in rats) limits tubular complement activation in proteinuric conditions. A relevant question to consider, which has important therapeutic ramifications, is whether complement activation occurs on normal tubules in glomerular proteinuria. The study by Hori et al suggests this is so, but does not prove it. To find proof, one has to turn to work in the same puromycin model performed by Nomura et al7Nomura A. Morita Y. Maruyama S. Hotta N. Nadai M. Wang L. Hasegawa M. Matsuo S. Role of complement in acute tubulointerstitial injury of rats with aminonucleoside nephrosis.Am J Pathol. 1997; 151: 539-547PubMed Google Scholar. In this study, animals that were complement depleted with cobra venom factor, or in which complement was inhibited with soluble recombinant CR1, had virtual elimination of complement activation, significantly less tubulointerstitial damage, and preserved paraaminohippuric acid (PAH) clearance. Similar findings were reported by this group using a model of mesangial proliferative glomerulonephritis8Morita Y. Nomura A. Yuzawa Y. Nishikawa K. Hotta N. Shimizu A. Matsuo S. The role of complement in the pathogenesis of tubulointerstitial lesions in rat mesangial proliferative glomerulonephritis.J Am Soc Nephrol. 1998; 8: 1363-1372Google Scholar. These studies show clearly that complement activation in experimental glomerular proteinuria leads to tubulointerstitial damage. Furthermore, complement inhibition with CR1 reduces this injury. These studies in rats are relevant to human disease. As stated above, the limited expression of complement regulators in tubular apical membranes is the case in both humans and rats. Complement deposits are present on tubular cells in human nephrotic syndrome, which at least provides circumstantial evidence that complement is activated9Camussi G. Stratta P. Mazzucco G. Gaido M. Tetta C. Castello R. Rotunno M. Vercellone A. In vivo localization of C3 on the brush border of proximal tubules of kidneys from nephrotic patients.Clin Nephrol. 1985; 23: 134-141PubMed Google Scholar. The use of antisense oligonucleotides to eliminate expression of a particular gene product was applied by Hori et al to show the role of Crry in tubular cells conclusively6Hori Y. Yamada K. Hanafusa N. Okuda T. Okada N. Miyata T. Couser W.G. Kurokawa K. Fujita T. Nangaku M. Crry, a complement regulatory protein, modulates renal interstitial disease induced by proteinuria.Kidney Int. 1999; 56: 2096-2106Abstract Full Text Full Text PDF PubMed Scopus (47) Google Scholar. The applicability of this therapy to renal diseases has exciting possibilities given the high degree of oligonucleotide uptake by endothelial cells, and by proximal tubular cells following glomerular filtration10Haller H. Maasch C. Dragun D. Wellner M. von Janta-Lipinski M. Luft F.C. Antisense oligodesoxynucleotide strategies in renal and cardiovascular disease.Kidney Int. 1998; 53: 1550-1558Abstract Full Text Full Text PDF PubMed Scopus (21) Google Scholar. However, its use in the particular setting of glomerular proteinuria is unlikely to be of benefit, as identifying a specific target gene to abolish is problematic. Given the likelihood that C5b-9 is pathogenic to tubules in these circumstances, targeting one of the terminal complement proteins is a conceivable approach, but liver synthesis would have to be eliminated. However, identifying other strategies to provide increased complement regulatory activity to tubules is very attractive. These include the use of pharmacological agents such as soluble recombinant human CR1 and humanized anti-C5 monoclonal antibodies11Wang Y. Hu Q. Madri J.A. Rollins S.A. Chodera A. Matis L.A. Amelioration of lupus-like autoimmune disease in NZB/W F1 mice after treatment with a blocking monoclonal antibody specific for complement component C5.Proc Natl Acad Sci USA. 1996; 93: 8563-8568Crossref PubMed Scopus (281) Google Scholar. Since both of these agents are now being used in Phase II trials for other diseases (including membranous nephropathy in the case of anti-C5 antibodies), their use to prevent progressive tubulointerstitial damage in nonselective glomerular proteinuria could be readily studied. Perhaps in the near future, but within the realm of possible, studies can be done to provide tubular epithelial cells with increased intrinsic complement regulatory activity. We have done such a maneuver in transgenic mice expressing soluble Crry driven by the metallothionein-I promoter that is highly expressed in tubules12Quigg R.J. He C. Lim A. Berthiaume D. Alexander J.J. Kraus D. Holers V.M. Transgenic mice overexpressing the complement inhibitor Crry as a soluble protein are protected from antibody-induced glomerular injury.J Exp Med. 1998; 188: 1321-1331Crossref PubMed Scopus (94) Google Scholar. These animals are protected in a model of complement-mediated tubular injury due to their overexpression of Crry. In summary, there is experimental evidence supporting that complement proteins pass the diseased glomerulus and can be activated on tubules. The resultant complement activation is detrimental and can lead to progressive tubulointerstitial injury. The current availability of recombinant protein inhibitors of complement should be exploited in an attempt to limit this progressive damage that ultimately can result in end-stage renal disease." @default.
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• W2019912184 title "We need to inhibit complement in glomerular proteinuria" @default.
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