NDT Advance Access originally published online on January 18, 2007
Nephrology Dialysis Transplantation 2007 22(5):1477; doi:10.1093/ndt/gfl804
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A novel renal perspective of preeclampsia: a look from the podocyte
Email: dhenao{at}medicina.udea.edu.coSir,
Preeclampsia (PE) is the most severe hypertensive complication of pregnancy. Onset of proteinuria is the main criterion for diagnosis of PE. Examination of renal biopsies of women with PE shows a pathognomonic lesion known as glomerular endotheliosis (GEN); nonetheless, GEN, from a low to a severe degree, has also been observed in women with gestational hypertension without proteinuria and in healthy pregnant women. Hence, alterations of renal function in women with PE can be attributed to a component of the glomerular filtration barrier (GFB) different from the glomerular endothelium. We propose that proteinuria in women with PE is due to direct injury of podocytes.
The GFB possesses three components: the glomerular endothelium, the glomerular basement membrane and epithelial cells known as podocytes. Podocytes assemble forming the slit diaphragm (SD). The SD is located between the foot processes of the podocytes and is composed of a protein complex including Nephrin, NEPH1, NEPH2, FAT1, P-cadherin, Podocin and CD2AP. These proteins interact with each other by way of the foot processes of other podocytes, forming a critical pathway of the GFB. Hence, down-regulation of one of these proteins could be involved in the appearance and development of proteinuria in women with PE. The function of the podocyte and the SD depends on the physiological concentrations of circulating factors, such as vascular endothelial growth factor (VEGF) and its antagonist, the soluble receptor fms-like tyrosine kinase 1 (sFlt-1).
Based on findings stating that, (i) GEN is present in women with PE and also in pregnant women without proteinuria, [1] (ii) physiological concentrations of VEGF are important for podocyte homeostasis and survival, [2] (iii) VEGF is important in maintaining of the SD by regulating nephrin expression, [3] (iv) sFlt-1 is a circulating antiangiogenic factor that antagonizes VEGF by binding to it and inactivating it, therefore inhibiting the action of VEGF on the SD, (v) there is an elevated concentration of sFlt-1 in the serum of women with PE as opposed to normotensive pregnant women, [4] (vi) elevated concentrations of sFlt-1 down-regulate the expression of proteins of the SD such as nephrin, [3] and (vii) down-regulation of nephrin expression leads to proteinuria, [5] we propose that proteinuria in patients with PE is mediated not only by endothelium alterations described classically, but also by disturbances of podocyte biology including impaired survival, enhanced apoptosis and down-regulation of nephrin and/or other key proteins of the SD.
Conflict of interest statement. None declared.
1Grupo Reproducción
Universidad de Antioquia
2Grupo de Patología Renal
y de Transplantes
3Grupo de Estudio Interdisciplinario
del Síndrome Hipertensivo
Asociado al Embarazo
Medellín
Colombia
4Academic Renal Unit
University of Bristol
Bristol, UK
References
- Strevens H, Wide-Swensson D, Hansen A, et al. (2003) Glomerular endotheliosis in normal pregnancy and pre-eclampsia. BJOG 110:831–836.[Web of Science][Medline]
- Foster RR, Saleem MA, Mathieson PW, Bates DO, Harper SJ. (2005) Vascular endothelial growth factor and nephrin interact and reduce apoptosis in human podocytes. Am J Physiol Renal Physiol 288:F48–57.
[Abstract/Free Full Text] - Sugimoto H, Hamano Y, Charytan D, et al. (2003) Neutralization of circulating vascular endothelial growth factor (VEGF) by anti-VEGF antibodies and soluble VEGF receptor 1 (sFlt-1) induces proteinuria. J Biol Chem 278:12605–12608.
[Abstract/Free Full Text] - Levine RJ, Maynard SE, Qian C, et al. (2004) Circulating angiogenic factors and the risk of preeclampsia. N Engl J Med 350:672–683.
[Abstract/Free Full Text] - Tryggvason K and Wartiovaara J. (2001) Molecular basis of glomerular permselectivity. Curr Opin Nephrol Hypertens 10:543–549.[CrossRef][Web of Science][Medline]
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