Original Report: Laboratory Investigation
Effects of 22-Oxa-Calcitriol on Podocyte Injury in Adriamycin-Induced NephrosisLydia A.a, b · Asanuma K.a · Nonaka K.a · Takagi M.a · Jeong K.-H.a, c · Kodama F.a · Asao R.a · Asanuma E.a · Prodjosudjadi W.b · Tomino Y.a
aDivision of Nephrology, Department of Internal Medicine, Juntendo University Faculty of Medicine, Tokyo, Japan; bDivision of Nephrology and Hypertension, Department of Internal Medicine, Cipto Mangunkusumo Hospital, University of Indonesia, Jakarta, Indonesia; cNephrology Division, Department of Internal Medicine, College of Medicine, Kyung Hee University, Seoul, Korea
Do you have an account?
- Rent for 48h to view
- Buy Cloud Access for unlimited viewing via different devices
- Synchronizing in the ReadCube Cloud
- Printing and saving restrictions apply
Rental: USD 8.50
Cloud: USD 20.00
Article / Publication Details
Background: In various animal studies, vitamin D has been shown to have a significant effect on reduction of proteinuria and the progression of kidney disease. However, little is known on its renoprotective effect in adriamycin (ADR)-induced nephrosis mice. The present study was intended to determine the therapeutic benefit of 22-oxa-calcitriol (OCT), a vitamin D analog, in reducing proteinuria and its renoprotective effect, i.e. preventing podocyte injury on ADR-induced nephrosis mice. Methods: Three experimental groups were used as follows: (1) nephrosis mice, established by a single intravenous injection of ADR; (2) ADR+OCT mice, nephrosis mice treated with OCT, and (3) mice treated only with OCT as the control group. Podocyte injury was assessed by podocyte apoptosis using the TUNEL assay, podocyte counting, podocyte-specific expressed protein by immunofluorescence and Western blot analysis, and foot process effacement using electron microscopy. Results: Lower proteinuria was observed in ADR+OCT mice. Improvement in glomerulosclerosis and interstitial fibrosis, and prevention of glomerular hyperfiltration were observed in ADR+OCT mice. Immunofluorescence and Western blot analyses showed restoration of downregulated expression of nephrin, CD2AP and podocin. Nevertheless, dendrin expression was not restored. An insignificant reduction in podocyte numbers was found in ADR+OCT mice. Complete foot process effacement was partially prevented in ADR+OCT mice. Conclusions: The results indicate that OCT reduces podocyte injury and has renoprotective effects in ADR nephrosis mice.
© 2011 S. Karger AG, Basel
- Kritz W, Lemley KV: The role of podocyte in glomerulosclerosis. Curr Opin Nephrol Hypertens 1999;8:489–497.
- Kerjaschki D: Caught flat-footed: podocyte damage and the molecular bases of focal glomerulosclerosis. J Clin Invest 2001;108:1583–1587.
- Shankland SJ: The podocyte’s response to injury: role in proteinuria and glomerulosclerosis. Kidney Int 2006;69:2131–2147.
- Maschio G, Alberti D, Janin G, Locatelli F, Mann JFE, Motolese M, Ponticelli C, Ritz E, Zucchelli P: Effect of the angiotensin converting enzyme inhibitor benazepril on the progression of chronic renal insufficiency. N Engl J Med 1996;334:939–945.
- Zoja C, Corna D, Camozzi D, Cattaneo D, Rottoli D, Batani C, Zanchi C, Abbate M, Remuzzi G: How to fully protect the kidney in a severe model of progressive nephropathy: a multidrug approach. J Am Soc Nephrol 2002;13:2898–2908.
- Ohara I, Tanimoto M, Gohda T, Yamazaki T, Hagiwara S, Murakoshi M, Aoki T, Toyoda H, Ishikawa Y, Funabiki K, Horikoshi S, Tomino Y: Effect of combination therapy with angiotensin receptor blocker and 1,25-dihydroxyvitamin D3 in type 2 diabetic nephropathy in KK-A(y)/Ta mice. Nephron Exp Nephrol 2011;117:e124–e132.
- Kuhlmann A, Haas CS, Gross M-L, Reulbach U, Holzinger M, Schwarz U, Ritz E, Amann K: 1,25-Dihydroxyvitamin D3 decreases podocyte loss and podocyte hypertrophy in the subtotally nephrectomized rat. Am J Physiol Renal Physiol 2004;286:F526–F533.
- Makibayashi K, Tatematsu M, Hirata M, Fukushima N, Kusano K, Ohashi S, Abe H, Kuze K, Fukatsu A, Kita T, Doi T: A vitamin D analog ameliorates glomerular injury on rat glomerulonephritis. Am J Pathol 2001;158:1733–1741.
- Panichi V, Migliori M, Taccola D, Filippi C, Nisco LD, Giovannini L, Palla R, Tetta C, Camussi G: Effects of 1,25(OH)2 D3 in experimental mesangial proliferative nephritis in rats. Kidney Int 2001;60:87–95.
- Schwarz U, Amann K, Orth SR, Simonaviciene A, Wessels S, Ritz E: Effect of 1,25 (OH)2 vitamin D3 on glomerulosclerosis in subtotally nephrectomized rat. Kidney Int 1998;53:1696–1705.
- Stumpf WE, Sar M, Reid FA, Tanaka Y, Deluca HF: Target cells for 1,25-dihydroxyvitamin D3 in intestinal tract, stomach, kidney, skin, pituitary, and parathyroid. Science 1979;206:1188–1190.
- Asanuma K, Akiba-Takagi M, Kodama F, Asao R, Nagai Y, Lydia A, Fukuda H, Tanaka E, Shibata T, Takahara H, Hidaka T, Asanuma E, Kominami E, Ueno T, Tomino Y: Dendrin location in podocytes is associated with disease progression in animal and human glomerulopathy. Am J Nephrol 2011;33:537–549.
- Tanimoto M, Fan Q, Gohda T, Shike T, Makita Y, Tomino Y: Effect of pioglitazone on the early stage of type 2 diabetic nephropathy in KK/Ta mice. Metabolism 2004;53:1473–1479.
- Schwarz K, Simons M, Reiser J, Saleem MA, Faul C, Kriz W, Shaw AS, Holzman LB, Mundel P: Podocin, a raft-associated component of the glomerular slit diaphragm, interacts with CD2AP and nephrin. J Clin Invest 2001;108:1583–1587.
- Asanuma K, Campbell KN, Kim K, Faul C, Mundel P: Nuclear relocation of the nephrin and CD2AP-binding protein dendrin promotes apoptosis of podocytes. PNAS 2007;104:10134–10139.
- Tang S, Leung J, Chan L, Eddy A, Lai K: Angiotensin converting enzyme inhibitor but not angiotensin receptor blockade or statin ameliorates murine adriamycin nephropathy. Kidney Int 2008;73:288–299.
- Sugiyama H, Kobayashi M, Wang D-H, Sunami R, Maeshima Y, Yamasaki Y, Masuoka N, Kira S, Makino H: Telmisartan inhibits both oxidative stress and renal fibrosis after unilateral obstruction in acatalasemic mice. Nephrol Dial Transplant 2005;20:2670–2680.
- Macconi D, Bonomelli M, Benigni A, Plati T, Sangalli F, Longaretti L, Conti S, Kawachi H, Hill P, Remuzzi G, Remuzzi A: Pathophysiologic implications of reduced podocyte number in a rat model of progressive glomerular injury. Am J Pathol 2006;1:42–54.
Asanuma K, Kim K, Oh J, Giardino L, Chabanis S, Faul C, Reiser J, Mundel P: Synaptopodin regulates the actin-bundling activity of alpha-actinin in an isoform-specific manner.. J Clin Invest 2005;5:1888–1198.
- Asanuma K, Tanida I, Shirato I, Ueno T, Takahara H, Nishitani T, Kominami E, Tomino Y: MAP-LC3, a promising autophagosomal marker, is processed during the differentiation and recovery of podocytes from PAN nephrosis. FASEB J 2003;17:1165–1187.
- Gassler N, Elger M, Kranzlin B, Kriz W, Gretz N, Hosser H, Hartmann I: Podocyte injury underlies the progression of focal segmental glomerulosclerosis in the fa/fa Zucker rat. Kidney Int 2001;60:106–116.
- Kim YH, Goyal M, Kurnit D, et al: Podocyte depletion and glomerulosclerosis have a direct relationship in the PAN-treated rat. Kidney Int 2001;60:957–968.
- Macconi D, Bonomelli M, Benigni A, Plati T, Sangalli F, Langaretti L, Conyi S, Kawachi H, Hill P, Remuzzi G, Remuzzi A: Pathophysiologic implications of reduced podocyte number in a rat model of progressive glomerular injury. Am J Pathol 2006;168:42–54.
- Mundel P, Shankland SJ: Podocyte biology and response to injury. J Am Soc Nephrol 2002;13:3005–3015.
- Wiggins R: The spectrum of podocytopathies: a unifying view of glomerular diseases. Kidney Int 2007;71:1205–1214.
- Kriz W, Gretz N, Lemley KV: Progression of glomerular diseases: is the podocyte the culprit? Kidney Int 1998;54:687–697.
- Asanuma K, Yanagida-Asanuma E, Takagi M, Kodama F, Tomino Y: The role of podocytes in proteinuria. Nephrology 2007;12:S15–S20.
- Migliori M, Giovannini L, Panichi V, Filippi C, Taccola D, Origlia N, Mannari C, Camussi G: Treatment with 1,25-dihydroxyvitamin D3 preserves glomerular slit diaphragm-associated protein expression in experimental glomerulonephritis. Int J Immunopathol Pharmacol 2005;18:779–790.
- Furness PN, Hall LL, Shaw JA, Pringle JH: Glomerular expression of nephrin is decreased in acquired human nephrotic syndrome. Nephrol Dial Transplant 1999;14:1234–1237.
- Toyoda M, Suzuki D, Umezono T: Expression of human nephrin mRNA in diabetic neph ropathy. Nephrol Dial Transplant 2004;19:380–385.
- Wang SX, Rastaldi MP, Patari A: Patterns of nephrin and new proteinuria-associated protein expression in human diseases. Kidney Int 2002;61:141–147.
- Zhang Z, Sun L, Wang Y, Ning G, Minto AW, Kong J, Quigg RJ, Li YC: Renoprotective role of the vitamin D receptor in diabetic nephropathy. Kidney Int 2008;73:163–171.
- Yamauchi K, Takano Y, Kasai A, Hayakawa K, Hiramatsu N, Enomoto N, Yao J, Kitamura M: Screening and identification of substances that regulate nephrin gene expression using engineered reporter podocytes. Kidney Int 2006;70:892–900.
- Asanuma K, Mundel P: The role of podocytes in glomerular pathobiology. Clin Exp Nephrol 2003;7:255–259.
- Yaddanapudi S, Altintas MM, Kistler A, Fernandez I, Moller CC, Wei C, Peev V, Flesche JB, Forst AL, Li J, Patrakka J, Xiao Z, Grahammer F, Schiffer M, Lohmuller T, Reinheckel T, Gu R, Huber TB, Ju W, Bitzer M, Rastaldi MP, Ruiz P, Tryggvason K, Shaw A, Faul C, Sever S, Reiser J: CD2AP in mouse and human podocytes controls a proteolytic program that regulates cytoskeletal structure and cellular survival. J Clin Invest 2011;121:3965–3980.
- Suarez IG, Redwood AB, Grotsky DA, Neumann MA, Cheng EHY, Stewart CL, Dusso A, Gonzalo S: A new pathway that regulates 53BP1 stability implicates Cathepsin L and vitamin D in DNA repair. EMBO J 2011;16:3383–3396.
- Xiao H, Shi W, Liu S, Wang W, Zhang B, Zhang Y, Xu L, Liang X, Liang Y: 1,25-Dihydroxyvitamin D3 prevents puromycin aminonucleoside-induced apoptosis of glomerular podocytes by activating the phosphatidylinositol 3-kinase/Akt-signaling pathway. Am J Nephrol 2009;30:34–43.
- Wagner N, Wagner KD, Schley G, Badiali L, Theres H, Scholz H: 1,25-dihydroxyvitamin D3-induced apoptosis of retinoblastoma cells is associated with reciprocal changes of Bcl-2 and bax. Exp Eye Res 2003;77:1–9.
Valrance ME, Welsh J: Breast cancer cell regulation by high-dose vitamin D compounds in the absence of nuclear vitamin D receptor. J Steroid Biochem Mol Biol 2004;89–90:221–225.
- Diker-Cohen T, Koren R, Liberman UA, Ravid A: Vitamin D protects keratinocytes from apoptosis induced by osmotic shock, oxidative stress, and tumor necrosis factor. Ann N Y Acad Sci 2003;1010:350–353.
Christakos S, Liu Y: Biological actions and mechanism of action of calbindin in the process of apoptosis. J Steroid Biochem Mol Biol 2004;89–90:401–404.
- Vertino AM, Bula CM, Chen JR, Almeida M, Han L, Bellido T, Kousteni S, Norman AW, Manolagan S: Nongenotropic, anti-apoptotic signaling of 1α,25(OH)2-vitamin D3 and analogs through the ligand binding domain of the vitamin D receptor in osteoblasts and osteocytes. J Biol Chem 2005;280:14130–14137.
- Freundlich M, Quiroz Y, Zhang Z, Zhang Y, Bravo Y, Weisinger JR, Li YC, Iturbe BR: Suppression of renin-angiotensin gene expression in the kidney by paricalcitol. Kidney Int 2008;74:1394–1402.
- Mizobuchi M, Morrissey J, Finch JL, Martin DR, Liapis H, Akizawa T, Slatopolsky E: Combination therapy with an angiotensin-converting enzyme inhibitor and a vitamin D analog suppresses the progression of renal insufficiency in uremic rats. J Am Soc Nephrol 2007;18:1796–1806.
- Rodriguez-Iturbe B, Romeo F, Johnson RJ: Pathophysiological mechanisms in salt-dependent hypertension. Am J Kidney Dis 2007;50:655–672.
- Furuichi T, Kawata S, Asoh Y, Kumaki K, Ohyama Y: Differential time course of induction of 1 alfa,25-dihydroxyvitamin D3–24 hydroxylase mRNA expression in rats by 1 alfa,25-dihydroxyvitamin D3 and its analogs. Life Sci 1998;62:453–459.
- Brown AJ, Finchi J, Grieff M, Ritter C, Kubodera N, Nishii Y, Slatopolsky E: The mechanism for the disparate actions of calcitriol and 22-oxacalcitriol in the intestine. Endocrinology 1993;133:1158–1164.
Article / Publication Details
Copyright / Drug Dosage / DisclaimerCopyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.