Anticubilin Antisense RNA Ameliorates Adriamycin-Induced Tubulointerstitial Injury in Experimental Rats

被引:12
作者
Liu, Jun [1 ]
Li, Kailong [1 ]
He, Yani [1 ]
Zhang, Jianguo [1 ]
Wang, Huiming [1 ]
Yang, Jurong [1 ]
Zhan, Jun [1 ]
Liang, Haijun [1 ]
机构
[1] Third Mil Med Univ, Daping Hosp, Inst Surg Res, Dept Nephrol, Chongqing 400042, Peoples R China
关键词
Gene delivery; Tubulointerstitial injury; Adriamycin; CHRONIC KIDNEY-DISEASE; MONOCYTE CHEMOATTRACTANT PROTEIN-1; CUBILIN-MEDIATED ENDOCYTOSIS; PROXIMAL TUBULAR CELLS; OVERLOAD PROTEINURIA; EPITHELIAL-CELLS; RENAL-DISEASE; MEGALIN; PATHOPHYSIOLOGY; NEPHROPATHY;
D O I
10.1097/MAJ.0b013e31821952a2
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
This study was designed to determine the effects of in vivo anticubilin antisense RNA on the uptake of albumin in tubules and on the tubulointerstitial injury in adriamycin-induced proteinuric rats. Adriamycin-treated rats were subjected to intrarenal delivery of adenoviral vectors encoding empty plasmid, cubilin sense RNA expression vector pAd-CUB or anticubilin antisense RNA expression vector pAd-ACUB on day 3. On days 14 and 28, half of the rats in each group were randomly selected to be killed, and blood samples, kidney tissues and 24-hour urine were collected. The diseased rats treated with pAdEasy-ACUB showed a 60% decrease in serum creatinine and glomerular filtration rate. Interestingly, the anticubilin antisense treatment led to a marked increase in albuminuria. Antisense treatment attenuated the histologic changes on both day 14 and day 28. The antisense treatment induced more than 60% recovery of adriamycin-induced injury, accompanied with 85% knockdown in the expression of cubilin protein and markedly decreased albumin deposition. Adriamycin induced an increase in the expression of monocyte chemoattractant protein-1, transforming growth factor-beta and regulated on activation in normal T-cell expressed and secreted and the number of infiltrating cells, which was reversed by the antisense treatment. Anticubilin antisense RNA delivered by an adenoviral vector ameliorates albuminuria-induced glomerulosclerosis and tubulointerstitial damage in adriamycin nephrotic rats, indicating that cubilin could be a potential therapeutic target in proteinuric nephropathy.
引用
收藏
页码:494 / 502
页数:9
相关论文
共 40 条
[1]   How does proteinuria cause progressive renal damage? [J].
Abbate, Mauro ;
Zoja, Carla ;
Remuzzi, Giuseppe .
JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY, 2006, 17 (11) :2974-2984
[2]   The Molecular Interactions between Filtered Proteins and Proximal Tubular Cells in Proteinuria [J].
Baines, Richard J. ;
Brunskill, Nigel J. .
NEPHRON EXPERIMENTAL NEPHROLOGY, 2008, 110 (02) :E67-E71
[3]   Targeted deletion of angiotensin II type 1A receptor does not protect mice from progressive nephropathy of overload proteinuria [J].
Benigni, A ;
Corna, D ;
Zoja, C ;
Longaretti, L ;
Gagliardini, E ;
Perico, N ;
Coffman, TM ;
Remuzzi, G .
JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY, 2004, 15 (10) :2666-+
[4]   Cubilin is an albumin binding protein important for renal tubular albumin reabsorption [J].
Birn, H ;
Fyfe, JC ;
Jacobsen, C ;
Mounier, F ;
Verroust, PJ ;
Orskov, H ;
Willnow, TE ;
Moestrup, SK ;
Christensen, EI .
JOURNAL OF CLINICAL INVESTIGATION, 2000, 105 (10) :1353-1361
[5]   Upregulation of K2P5.1 Potassium Channels in Multiple Sclerosis [J].
Bittner, Stefan ;
Bobak, Nicole ;
Herrmann, Alexander M. ;
Goebel, Kerstin ;
Meuth, Patrick ;
Hoehn, Karin G. ;
Stenner, Max-Philipp ;
Budde, Thomas ;
Wiendl, Heinz ;
Meuth, Sven G. .
ANNALS OF NEUROLOGY, 2010, 68 (01) :58-69
[6]   Role of megalin and cubilin in renal physiology and pathophysiology [J].
Christensen, E. I. ;
Nielsen, R. .
REVIEWS OF PHYSIOLOGY, BIOCHEMISTRY AND PHARMACOLOGY, VOL 158, 2007, 158 :1-22
[7]   Megalin and cubilin: Multifunctional endocytic receptors [J].
Christensen, EI ;
Birn, H .
NATURE REVIEWS MOLECULAR CELL BIOLOGY, 2002, 3 (04) :258-268A
[8]   Targeting proteinuria as a valid surrogate for individualized kidney protective therapy [J].
de Zeeuw, Dick .
AMERICAN JOURNAL OF KIDNEY DISEASES, 2008, 51 (05) :713-716
[9]   Antiproteinuric effect of ciclosporin A in adriamycin nephropathy in rats [J].
Desassis, JF ;
Raats, CJI ;
Bakker, MAH ;
vandenBorn, J ;
Berden, JHM .
NEPHRON, 1997, 75 (03) :336-341
[10]   The role of capillary density, macrophage infiltration and interstitial scarring in the pathogenesis of human chronic kidney disease [J].
Eardley, Kevin S. ;
Kubal, Chandrashekhar ;
Zehnder, Daniel ;
Quinkler, Marcus ;
Lepenies, Julia ;
Savage, Caroline O. ;
Howie, Alec J. ;
Kaur, Kirrenjit ;
Cooper, Mark S. ;
Adu, Dwomoa ;
Cockwell, Paul .
KIDNEY INTERNATIONAL, 2008, 74 (04) :495-504