The

glomerular basement membrane and the podocytes are typically not affected as seen in electron microscopic images. However, despite the lack of microscopic evidence of podocyte damage, there are data that podocytes have a role in preeclampsia. Podocyturia has been RG7420 purchase demonstrated in patients with glomerular diseases.55 More recently women with clinically established preeclampsia have been shown to excrete viable podocytes in their urine56,57 called ‘footprints in the urine’.58 Women with normotensive pregnancies and women with gestational hypertension did not have podocyturia. The significance of these results remains to be confirmed in larger clinical studies. Molecular and cellular studies by Garovic and others have shown marked downregulation of podocyte expression of nephrin and synaptopodin

and this combined with the endothelial cell injury is likely to explain the proteinuria.47 The possible mechanism of the proteinuria is that the decrease in nephrin is due to its release from the slit diaphragm by proteolytic cleavage.59,60 Nephrin shedding could be due to increased endothelin61 and decreased VEGF62 both of which are implicated in the endothelial injury. The recent finding of the reduced availability of podocyte-produced VEGF indicates a mechanism whereby the endothelium loses its fenestrations and this alteration contributes to protein loss in the urine.63–66 In this instance, there is reduction in endothelial signalling and subsequent endothelial swelling, and thus a reduction in both

the size and density Wnt inhibitor Resveratrol of the fenestrations on the endothelial cells.65 The hypothesis therefore is that the endothelial injury is the primary insult and that podocyte damage directly results from these events. An increase in circulating sFLT-1 (soluble VEGF receptor) reduces the available free VEGF, resulting in an increase in endothelin-1 production and secretion by the glomerular endothelial cell61 (Fig. 2). The animal model of proteinuria in which antibodies to VEGF are infused into rats66 confirms podocyte damage as well as endothelial dysfunction.62,65 The importance of the endothelial cell/podocyte interrelationship is further evidenced by the effect of circulating sFLT-1 binding podocyte-produced VEGF resulting in endothelial thickening, which may be responsible for the reduction in both the size and the density of endothelial fenestrations.66 Other potential mechanisms include CD2AP, epithelial protein 1, GLEPP, Twerk and cytokines,34,67 but their roles are not fully elucidated. The proteinuria per se may be damaging to podocyte function.68,69 Given the profound haemodynamic renal adaptation required for normal pregnancy, it is no wonder that underlying renal disease poses a particular risk in pregnancy.