Abstract
To study the effects of podocyte injury on glomerular maturation and underlying mechanisms of such effects, puromycin aminonucleoside (PAN) was given to neonatal mice at 1 d post partum (1 dpp). Mice with PAN injection had smaller kidney weight (KW) and body weight (BW) at all times and smaller KW/BW at 4, 8, and 12 dpp versus normal saline (NS) controls. Electron microscopy (EM) revealed nearly complete podocyte foot process effacement and segmental microvillous transformation as early as 2 dpp, preceding proteinuria. PAN-injected kidneys showed significantly fewer glomerular capillary loops and decreased glomerular maturation index, as well as less CD31+ endothelium in cortical glomeruli at 12 dpp versus NS controls. Glomerular mesangial injury and glomerulosclerosis along with proteinuria were noted in PAN-injected kidneys starting from 30 dpp. Systolic blood pressure was increased significantly by 60 dpp in PAN mice. PAN mice also had significantly decreased Flk-1 and Tie2 mRNA expression and increased angiopoitein-1 (Ang-1) expression, without change in vascular endothelial growth factor (VEGF) at 2 dpp versus NS. Our study shows that podocyte injury in neonatal mice kidneys alters the expression of key capillary growth modulators in glomeruli, leading to abnormal development of glomerular capillaries, with subsequent development of proteinuria, hypertension, and glomerulosclerosis.
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Abbreviations
- Ang-1:
-
angiopoietin-1
- dpp:
-
days postpartum
- EM:
-
electron microscopy
- GBM:
-
glomerular basement membrane
- KW:
-
kidney weight
- NS:
-
normal saline
- PAN:
-
puromycin aminonucleoside
- VEGF:
-
vascular endothelial growth factor
- WT-1:
-
Wilms tumor suppressor gene 1
References
Camici M 2005 Renal glomerular permselectivity and vascular endothelium. Biomed Pharmacother 59: 30–37
Simon M, Grone HJ, Johren O, Kullmer J, Plate KH, Risau W, Fuchs E 1995 Expression of vascular endothelial growth factor and its receptors in human renal ontogenesis and in adult kidney. Am J Physiol 268: F240–F250
Satchell SC, Harper SJ, Tooke JE, Kerjaschki D, Saleem MA, Mathieson PW 2002 Human podocytes express angiopoietin 1, a potential regulator of glomerular vascular endothelial growth factor. J Am Soc Nephrol 13: 544–550
Takazawa Y, Maeshima Y, Kitayama H, Yamamoto Y, Kawachi H, Shimizu F, Matsui H, Sugiyama H, Yamasaki Y, Makino H 2005 Infusion of angiotensin II reduces loss of glomerular capillary area in the early phase of anti-Thy-1.1 nephritis possibly via regulating angiogenesis-associated factors. Kidney Int 68: 704–722
Masuda Y, Shimizu A, Mori T, Ishiwata T, Kitamura H, Ohashi R, Ishizaki M, Asano G, Sugisaki Y, Yamanaka N 2001 Vascular endothelial growth factor enhances glomerular capillary repair and accelerates resolution of experimentally induced glomerulonephritis. Am J Pathol 159: 599–608
Yuan HT, Tipping PG, Li XZ, Long DA, Woolf AS 2002 Angiopoietin correlates with glomerular capillary loss in anti-glomerular basement membrane glomerulonephritis. Kidney Int 61: 2078–2089
Majumdar A, Drummond IA 1999 Podocyte differentiation in the absence of endothelial cells as revealed in the zebrafish avascular mutant, cloche. Dev Genet 24: 220–229
Majumdar A, Drummond IA 2000 The zebrafish floating head mutant demonstrates podocytes play an important role in directing glomerular differentiation. Dev Biol 222: 147–157
Kitamoto Y, Tokunaga H, Tomita K 1997 Vascular endothelial growth factor is an essential molecule for mouse kidney development: glomerulogenesis and nephrogenesis. J Clin Invest 99: 2351–2357
Eremina V, Sood M, Haigh J, Nagy A, Lajoie G, Ferrara N, Gerber HP, Kikkawa Y, Miner JH, Quaggin SE 2003 Glomerular-specific alterations of VEGF-A expression lead to distinct congenital and acquired renal diseases. J Clin Invest 111: 707–716
Vega-Warner V, Ransom RF, Vincent AM, Brosius FC, Smoyer WE 2004 Induction of antioxidant enzymes in murine podocytes precedes injury by puromycin aminonucleoside. Kidney Int 66: 1881–1889
Niimura F, Labosky PA, Kakuchi J, Okubo S, Yoshida H, Oikawa T, Ichiki T, Naftilan AJ, Fogo A, Inagami T, Hogan BL, Ichikawa I 1995 Gene targeting in mice reveals a requirement for angiotensin in the development and maintenance of kidney morphology and growth factor regulation. J Clin Invest 96: 2947–2954
Livak KJ, Schmittgen TD 2001 Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods 25: 402–408
Ploplis VA, Balsara R, Sandoval-Cooper MJ, Yin ZJ, Batten J, Modi N, Gadoua D, Donahue D, Martin JA, Castellino FJ 2004 Enhanced in vitro proliferation of aortic endothelial cells from plasminogen activator inhibitor-1-deficient mice. J Biol Chem 279: 6143–6151
Zhang ZG, Zhang L, Tsang W, Soltanian-Zadeh H, Morris D, Zhang R, Goussev A, Powers C, Yeich T, Chopp M 2002 Correlation of VEGF and angiopoietin expression with disruption of blood-brain barrier and angiogenesis after focal cerebral ischemia. J Cereb Blood Flow Metab 22: 379–392
Roselli S, Heidet L, Sich M, Henger A, Kretzler M, Gubler MC, Antignac C 2004 Early glomerular filtration defect and severe renal disease in podocin-deficient mice. Mol Cell Biol 24: 550–560
Adler S 1992 Characterization of glomerular epithelial cell matrix receptors. Am J Pathol 141: 571–578
Kriz W 2002 Podocyte is the major culprit accounting for the progression of chronic renal disease. Microsc Res Tech 57: 189–195
Sasaki T, Osawa G 1993 A kinetic study of the glomerular cells of developing and mature rat kidneys using an anti-bromodeoxyuridine monoclonal antibody. Nippon Jinzo Gakkai Shi 35: 1213–1219
Hyink DP, Abrahamson DR 1995 Origin of the glomerular vasculature in the developing kidney. Semin Nephrol 15: 300–314
Pinto JA, Brewer DB 1975 Combined light and electron-microscope morphometric studies of acute puromycin aminonucleoside nephropathy in rats. J Pathol 116: 149–164
Glasser RJ, Velosa JA, Michael AF 1977 Experimental model of focal sclerosis. I. Relationship to protein excretion in aminonucleoside nephrosis. Lab Invest 36: 519–526
Fogo AB 2003 Animal models of FSGS: lessons for pathogenesis and treatment. Semin Nephrol 23: 161–171
Wang L, Fields TA, Pazmino K, Dai Q, Burchette JL, Howell DN, Coffman TM, Spurney RF 2005 Activation of G{alpha}q-coupled signaling pathways in glomerular podocytes promotes renal injury. J Am Soc Nephrol 16: 3611–3622
Macconi D, Bonomelli M, Benigni A, Plati T, Sangalli F, Longaretti L, Conti S, Kawachi H, Hill P, Remuzzi G, Remuzzi A 2006 Pathophysiologic implications of reduced podocyte number in a rat model of progressive glomerular injury. Am J Pathol 168: 42–54
Wolf G, Chen S, Ziyadeh FN 2005 From the periphery of the glomerular capillary wall toward the center of disease: podocyte injury comes of age in diabetic nephropathy. Diabetes 54: 1626–1634
Yu D, Petermann A, Kunter U, Rong S, Shankland SJ, Floege J 2005 Urinary podocyte loss is a more specific marker of ongoing glomerular damage than proteinuria. J Am Soc Nephrol 16: 1733–1741
Ortmann J, Amann K, Brandes RP, Kretzler M, Munter K, Parekh N, Traupe T, Lange M, Lattmann T, Barton M 2004 Role of podocytes for reversal of glomerulosclerosis and proteinuria in the aging kidney after endothelin inhibition. Hypertension 44: 974–981
Acknowledgements
The authors thank Xiaofeng Fan for excellent technical assistance.
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This work was supported by the National Institutes of Health grants DK-44757 and DK-37868, the Ministry of Education of China grant 81038 and the National Natural Science Foundation of China grant 30200125.
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Ma, J., Rossini, M., Yang, HC. et al. Effects of Podocyte Injury on Glomerular Development. Pediatr Res 62, 417–421 (2007). https://doi.org/10.1203/PDR.0b013e31813cbed1
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DOI: https://doi.org/10.1203/PDR.0b013e31813cbed1
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