TY - JOUR
T1 - Crry, a complement regulatory protein, modulates renal interstitial disease induced by proteinuria
AU - Hori, Yuichi
AU - Yamada, Koei
AU - Hanafusa, Norio
AU - Okuda, Toshihiro
AU - Okada, Noriko
AU - Miyata, Toshio
AU - Couser, William G.
AU - Kurokawa, Kiyoshi
AU - Fujita, Toshiro
AU - Nangaku, Masaomi
N1 - Funding Information:
M.N. is a recipient of an award from the Sankyo Foundation of Life Science and an award from the Takeda Science Foundation. This work was also supported by Grants in Aid for Scientific Research from the Ministry of Education, Science and Culture (#02404036 and 05404041 to K.K.) and by Research Grants for the U.S. National Institutes of Health (DK34198 and DK07467 to W.G.C.). We gratefully acknowledge the useful advice of Dr. Richard J. Quigg (University of Chicago, Chicago, IL, USA), Dr. Seiichi Matsuo (University of Nagoya, Nagoya, Japan), and Dr. Nobuhiko Joki (Toho University School of Medicine, Tokyo, Japan). Part of this work was presented in a preliminary form at the 31st Annual Meeting of the American Society of Nephrology, Philadelphia, PA, USA, October 25–28, 1998.
PY - 1999
Y1 - 1999
N2 - Background. Recent studies have suggested a role for urinary complement components in mediating tubulointerstitial damage, which is known to have a good correlation with progression of chronic renal diseases. Although accumulating evidence suggests that complement regulatory proteins play an important protective role in glomeruli, their role in renal tubules remains unclear. In order to establish the role of a complement regulatory protein, Crry, in renal tubular injury, we employed a molecular biological approach to block the expression of Crry in tubules of animals with proteinuria induced with puromycin aminonucleoside nephritis (PAN). Methods and Results. Two different antisense oligodeoxynucleotides (ODNs) against Crry were designed and applied to cultured rat mesangial cells in vitro in order to establish their efficacy. Antisense ODN treatment resulted in decreased expression of Crry protein associated with increased sensitivity to complement attack in cell lysis assays compared with control ODN treatment or no treatment (44.7, 1.50, and 1.34%, respectively). Antisense ODNs did not affect the expression of Thy1 as a control, confirming the specificity of our ODNs. In vivo, we performed selective right renal artery perfusion to administer antisense ODNs to the kidney and showed prominent uptake of ODNs by proximal tubular cells. Reduced expression of Crry protein was demonstrated in proximal tubular cells in antisense ODNs-treated kidneys. Normal rats treated with the antisense ODNs did not show any pathological changes. However, in PAN, rats with massive proteinuria showed increased deposition of C3 and C5b-9 in tubules in antisense-treated kidneys, and histological assessment revealed more severe tubulointerstitial injury in antisense-treated animals compared with controls. Conclusion. These results establish a pathogenic role for complement in leading to tubulointerstitial injury during proteinuria and, to our knowledge for the first time, show a protective role of a complement regulatory protein, Crry, in renal interstitial disease.
AB - Background. Recent studies have suggested a role for urinary complement components in mediating tubulointerstitial damage, which is known to have a good correlation with progression of chronic renal diseases. Although accumulating evidence suggests that complement regulatory proteins play an important protective role in glomeruli, their role in renal tubules remains unclear. In order to establish the role of a complement regulatory protein, Crry, in renal tubular injury, we employed a molecular biological approach to block the expression of Crry in tubules of animals with proteinuria induced with puromycin aminonucleoside nephritis (PAN). Methods and Results. Two different antisense oligodeoxynucleotides (ODNs) against Crry were designed and applied to cultured rat mesangial cells in vitro in order to establish their efficacy. Antisense ODN treatment resulted in decreased expression of Crry protein associated with increased sensitivity to complement attack in cell lysis assays compared with control ODN treatment or no treatment (44.7, 1.50, and 1.34%, respectively). Antisense ODNs did not affect the expression of Thy1 as a control, confirming the specificity of our ODNs. In vivo, we performed selective right renal artery perfusion to administer antisense ODNs to the kidney and showed prominent uptake of ODNs by proximal tubular cells. Reduced expression of Crry protein was demonstrated in proximal tubular cells in antisense ODNs-treated kidneys. Normal rats treated with the antisense ODNs did not show any pathological changes. However, in PAN, rats with massive proteinuria showed increased deposition of C3 and C5b-9 in tubules in antisense-treated kidneys, and histological assessment revealed more severe tubulointerstitial injury in antisense-treated animals compared with controls. Conclusion. These results establish a pathogenic role for complement in leading to tubulointerstitial injury during proteinuria and, to our knowledge for the first time, show a protective role of a complement regulatory protein, Crry, in renal interstitial disease.
KW - Antisense oligonucleotides
KW - Interstitial nephritis
KW - Nephrotic syndrome
KW - Progressive renal disease
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U2 - 10.1046/j.1523-1755.1999.00765.x
DO - 10.1046/j.1523-1755.1999.00765.x
M3 - Article
C2 - 10594785
AN - SCOPUS:0033405957
SN - 0085-2538
VL - 56
SP - 2096
EP - 2106
JO - Kidney International
JF - Kidney International
IS - 6
ER -