2 role in the pathogenesis of podocytopathies. Changes in nephrin, as well as in the nephrin homologue Neph1 [13], in CD2-associated protein (CD2AP) [14, 15], in mFAt1 [16], or in podocin [17] have been described. Autosomal recessive changes in NPHS2 gene causes steroid-resistant nephrotic syndrome [12, 18, 19]. NPHS2 gene polymorphisms cause proteinuria in patients with minimal change disease (MCD) [20]. It has been proposed that apoptosis, necrosis, or loss of cellular adhesive interaction induce podocyte detachment from the GBM, playing a central role in the FSGS-mediated hyperﬁltration process. Modiﬁcations in the foot process cytoskeleton may lead to nephrotic syndrome development, being podocalyxin believed to be responsible for foot pro- cess stability [21, 22]. Another component of the luminal membrane is a transmembrane tyrosine-phosphatase named GLEPP-1, which might function as a receptor [23] or regulate both the pressure and the ﬁltration rates [24]. The expression of GLEPP-1 seems to be downregulated in patients with FSGS and collapsing glomerulopathy but at normal levels in MCD cases [25]. It has been recently demonstrated that podocalyxin is increased in nephrotic syndromes [26]. The pathogenesis of glomerular sclerosis seen in FSGS might to be caused by an increase in glomerular proﬁbrotic cytokines, such as IL-13 and IL-4 [27–30], whereas other studies suggested the increase of TGF-β levels in this process [30, 31]. The TGF-β pathway controls cellular responses to many chronic glomerular injuries, thereby leading to an increase in the production of extracellular matrix, an increase in podocyte number and area, and apoptosis [32–37]. The TGF-β signaling pathway may act as a key mediator in cellular mechanisms responsible for glomerulosclerosis and interstitial ﬁbrosis [35]. A mediator of TGF-β signaling, Smad7, is strongly expressed in clinical cases of podocyte injury. In vitro culture of mice podocytes in the presence of TGF-β showed that both Smad7 and TGF-SS1 are related to cell apoptosis, suggesting that Smad7 participates in the progressive reduction of podocytes [38]. Some studies have shown that higher renal expression of TGF-β1 would be observed in children with FSGS in comparison to patients with MCD. This ﬁnding suggests that TGF-β1 gene transcription in the kidneys may suggest the development of FSGS renal lesions [39]. Evidences suggested that podocytes may succumb the epithelial-mesenchymal transition (EMT) after antigenic encounter. In this phenomenon, podocytes lack their speciﬁc epithelial cell markers such as nephrin, P-cadherin, and zonula occludens-1 and acquire markers speciﬁc for mes- enchymal cells such as desmin, ﬁbroblast-speciﬁc protein- 1, matrix metalloproteinase-9, type I collagen, α-smooth muscle actin, and ﬁbronectin. These changes may lead to a damage in glomerular ﬁltration barrier, which results in proteinuria [40–42]. Elevated TGF-β1 production might induce the expres- sion of integrin-linked kinase (ILK), a protein that is related to the pathogenesis of many nephropathies that course with proteinuria. The upregulation of ILK in the podocytes may determine the occurrence of EMT in these cells via snail transcription factor induction [43]. International Journal of Nephrology Podocytes of patients with FSGS and membranous nephropathy present lower expression of nephrin mRNA than cells from patients with MCD [44]. Apparently, EMT events are more frequently associated to FSGS and membra- nous nephropathy than to MCD. Nephrin is an important component of the slit dia- phragm. It also functions as a potent recruiter of other proteins to podocyte membrane such as podocin and CD2AP [45]. Intracellular domains of the nephrin protein are tyrosine phosphorylated by Src family kinases [46]. The phosphorylated tyrosine residues of nephrin might bind to Nck adaptor proteins and consequently induce a local polymerization of actin [47, 48]. In adult mice, it has been shown that inhibition of Nck expression in podocytes, promoted a fast induction of proteinuria, glomerulosclerosis, and the morphological changes observed in foot processes. These results suggest that Nck proteins might contribute to keep intact the glomerular ﬁltration barrier in adults [49]. The foot processes are composed by actin cytoskele- ton which main components are actin itself, α-actinin, and synaptopodin [50, 51]. Some nephrotic syndromes may present a cytoskeleton reorganization after upregula- tion of α-actinin [21]. Dominant mutations in α-actinin- 4 (ACTN4) gene are associated with FSGS occurrence [52]. The expression of synaptopodin is generally pre- served in nephrotic syndromes as MCD, but reduced in FSGS [53]. The expression of other podocyte cytoskeleton- bound proteins, such as the dystroglycans, are kept unaltered in FSGS, but decreased in active MCD [54]. Some studies suggest an important interaction between actin cytoskeleton structure and some components of the slit diaphragm as podocin, nephrin and CD2AP [55, 56]. The nephrotic syndromes are known by their changes in podocytes as the eﬀacement of podocyte foot processes, as well as structural changes in cytoskeleton and molecular reorganization of slit diaphragm [57]. The B7-1 molecule (CD80) is a transmembrane protein commonly encountered only in the cell surface of B lymphocytes and antigen presenting cells [58–60]. Reiser et al. have shown that under stress conditions B7-1 might be expressed on podocytes, which may cause reorganization of actin cytoskeleton and modulation of molecules component of the slit diaphragm [61]. It suggests that B7-1 might be directly involved in the pathogenesis of the nephrotic syndrome. Sometimes the diﬀerentiation between FSGS and MCD cases is very diﬃcult, mainly when renal biopsies present inadequate numbers of glomeruli. In such cases, the typical FSGS focal sclerosis is unable to be evidenced [4]. In these cases, the discovery of other markers is urgently needed. Malondialdehyde is a lipid peroxidation marker induced by oxidative stress that may occur in acute or chronic nephropathies [62, 63]. It has been observed that urinary and serum levels of malondialdehyde as well as its glomerular expression were elevated in patients with FSGS when compared to MCD cases [64, 65]. This indicates that tissue expression of oxidative stress markers should be considered as diﬀerential diagnostic tools.