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NDT Advance Access originally published online on January 25, 2007
Nephrology Dialysis Transplantation 2007 22(4):1136-1143; doi:10.1093/ndt/gfl711
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© The Author [2007]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Glomerular expression of nephrin and synaptopodin, but not podocin, is decreased in kidney sections from women with preeclampsia

Vesna D. Garovic1, Steven J. Wagner1, Lydia M. Petrovic2, Catherine E. Gray1, Pauline Hall3, Hikaru Sugimoto4, Raghu Kalluri4 and Joseph P. Grande1

1Division of Nephrology and Hypertension, Mayo Medical College, Rochester, MN, USA, 2Department of Pathology, New York University, New York, NY, USA, 3Department of Pathology, University of Cape Town, South Africa and 4Center for Matrix Biology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA

Correspondence and offprint requests to: Vesna D. Garovic, Division of Nephrology and Hypertension Mayo Clinic, 200 First Street SW, Rochester, Minnesota, 55905, USA. Email: garovic.vesna{at}mayo.edu



   Abstract
Top
 Abstract
Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 
Background. Preeclampsia is a pregnancy-specific disorder characterized by hypertension and proteinuria. In other disease states, proteinuria has been linked to altered expressions of podocyte foot-process proteins, but this has not been studied in women with preeclampsia. We sought to test the hypothesis that proteinuria in preeclampsia is associated with dysregulated expression of the podocyte cytoskeleton and/or tight junction proteins.

Mathods. Renal tissue was obtained from autopsy material from seven women who had severe preeclampsia during the second half of their pregnancies up to 48 h after delivery, and who subsequently died. As controls, we used autopsy material from two women who died accidentally during the second half of their otherwise normal pregnancies. Immunohistochemical stains for nephrin, synaptopodin and podocin were performed on representative sections prepared from paraffin-embedded material.

Results. Expression of both nephrin and synaptopodin was markedly decreased in preeclamptic compared with control kidney sections. By contrast, both cases and controls demonstrated strong staining for podocin.

Conclusions. We conclude that down-regulation of nephrin and synaptopodin is associated with proteinuria in women with preeclampsia. Recent studies have demonstrated that soluble vascular endothelial growth factor receptor 1 (sFlt-1) levels are elevated in preeclampsia compared with normal pregnancy. Studies in mice have shown that sFlt-1 may play a role in inducing proteinuria by neutralizing vascular endothelial growth factor (VEGF) and suppressing nephrin. Proteinuria and elevations of sFlt-1 in preeclampsia are temporally related, further supporting a possible role of sFlt-1 in the dysregulation of podocyte foot-process proteins.

Keywords: nephrin; parietal epithelial cell; podocin; preeclampsia; proteinuria; slit diaphragm; synaptopodin



   Introduction
Top
 Abstract
 Introduction
Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 
Preeclampsia is a pregnancy-specific disorder clinically characterized by hypertension and proteinuria that occurs after 20 weeks of gestation. It affects approximately 5% of all pregnancies and remains a leading cause of both maternal and fetal morbidity and mortality worldwide [1]. The aetiology and pathogenesis of this condition remain elusive, resulting in a failure to develop specific preventive and treatment strategies. Several studies have provided evidence that preeclampsia is associated with elevated levels of the soluble receptor for vascular endothelial growth factor (VEGF) [2,3], commonly referred to as sFlt-1 (from soluble, fms-like tyrosine kinase receptor-1) that may bind and neutralize VEGF. Elevations in sFlt-1 levels have been shown to correlate with both the severity of the disease [4,5] and the degree of proteinuria [6]. While studies in mice treated with intravenous infusion of sFlt-1 have shown that a possible mechanism of proteinuria relates to down-regulation of nephrin, a structural component of the epithelial slit diaphragm [7], no data are available regarding the expression of nephrin in kidney tissues of preeclamptic women.

The aim of this study was to test the hypothesis that proteinuria is associated with down-regulation of nephrin in the kidneys from women with preeclampsia. Mutations in the nephrin (NPHS1) gene have been found in patients with congenital nephrotic syndrome of the Finnish type [8]. In addition to nephrin, we studied two other proteins that localize either to the slit diaphragm (podocin) or to the foot-process cytoskeleton (synaptopodin), as studies of the nephrotic syndrome in humans have indicated that these proteins play important roles in maintaining the structural and functional integrity of the slit diaphragm. Mutations in the gene coding for podocin (NPHS2) result in recessive familial forms of early onset proteinuria, resistant to steroid treatment [9]. Podocin may regulate the structural organization and filtration function of the slit diaphragm by interacting directly with nephrin [10]. Synaptopodin is an actin-associated protein, which is linked to the formation of foot processes, a hallmark of the differentiated podocyte phenotype [11]. Comparative studies of synaptopodin expression in human glomerulopathies have suggested that the disappearance of synaptopodin may serve as a prognostic indicator [12]: expression is normal in minimal change disease, which is usually reversible and associated with a benign course, and absent in collapsing nephropathies (idiopathic and HIV-associated) which are known for their progressive characters. As kidney biopsies are rarely performed during preeclampsia, we studied the expressions of these proteins in the kidney sections obtained from the autopsy material of women who died from preeclampsia. In addition, we studied expression of synaptopodin in kidney sections from mice treated with either anti-VEGF antibody or sFlt-1. This animal model has been shown to develop proteinuria presumably through the down-regulation of nephrin [7], while the expression of synaptopodin has not yet been reported.



   Materials and methods
Top
 Abstract
 Introduction
 Materials and methods
Results
 Discussion
 Acknowledgements
 References
 
Human renal tissue experiments
Renal tissue was obtained from the autopsy materials from seven women who developed severe preeclampsia during the second half of their pregnancies up to 48 h after delivery, and who subsequently died (Table 1). As controls, we used autopsy material from two women who died accidentally during the second half of their otherwise normal pregnancies. Kidney sections for six cases (cases 1–6) were obtained through collaboration with the University of Cape Town, South Africa; one case (case 7) and both controls were obtained through the Department of Pathology at Mayo Clinic. Light microscopy and immunohistochemical stains for nephrin, synaptopodin and podocin were performed on representative sections prepared from paraffin-embedded material.


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  		Table 1. Clinical presentations and outcomes of seven cases of preeclampsia and two controls

 
Preeclampsia was defined as a pregnancy-specific disorder characterized by hypertension (blood pressure ≥ 140/90 mmHg) and proteinuria ≥ 300 mg/24 h urine, which roughly correlates with a qualitative measurement of 1 + (30 mg/dl) on dipstick urinalysis. The convulsive form of preeclampsia, i.e. eclampsia, was diagnosed in four patients who presented with seizures up to 48 h after delivery. HELLP syndrome, a severe form of preeclampsia clinically characterized by haemolysis, elevated liver enzymes, and low platelet count, was confirmed in three cases based on the following criteria [13]: (i) Evidence of intravascular haemolysis [decreasing haemoglobin, abnormal peripheral blood smear (schistocytes), elevated lactate dehydrogenase (LDH), elevated total bilirubin], (ii) Elevated liver enzymes [alanine transaminase, aspartate transaminase and LDH, (iii) Low platelet count (<100 x 109/l).

Immunocytochemistry
All studied samples were obtained during autopsies: renal tissue was fixed in 10% neutral buffered formalin, dehydrated and embedded in paraffin per standard techniques. Representative samples were stored at room temperature between 5 (case #2) and up to 50 years (case #3) (Table 1). Histological sections, 4–5 µm thick, were prepared. Representative sections were stained with nephrin (Alpha Diagnostic International), synaptopodin (Biodesign) and podocin (Alpha Diagnostics, International) antibodies. Antigen retrieval was performed by steam heating in 0.5 mmol EDTA for 30 min (for nephrin and synaptopodin), followed by enzyme treatment with trypsin for 10 min at 37°C (nephrin, synaptopodin and podocin). Commercially available kits (Vectastain ABC kit, Vector Laboratories and Envision Plus HRP kit, DakoCytomation) were used for blocking, secondary antibody, and amplification steps. Color development was performed using NovaRed (Vector Laboratories) followed by haematoxylin counterstain. To facilitate consistency between staining batches, most of the stains were performed on the DakoAutostainer, an automated staining machine.

Animal experiments
Anti-VEGF antibody and sFlt-1 studies were performed using wild-type CD1 mice, as previously described [7]. Briefly, five mice in each group were injected with a single intravenous injection of either anti-VEGF antibody or a soluble sFlt-1/Fc chimera at a concentration of 32.5 pM (picomole per litre), which corresponds to 10 times the molar concentration of normal plasma VEGF (3.25 pM). One hundred microlitres of urine were collected at 0, 1, 3, 5 and 24 h after the initial injection. Mice developed significant proteinuria 3 h after the intravenous injections and maintained the same level of proteinuria for the subsequent 7 h. The amount of proteinuria gradually abated to normal urine protein levels within 24 h. Some mice were sacrificed 5 h after the injection to collect kidneys for immunocytochemistry. Mice injected with IgG served as a control. In rescue experiments, 32.5 pM of human recombinant VEGF-165 was injected about 5 min after the injection of the VEGF antibody or sFlt-1/Fc. Immunofluorescence staining was performed for nephrin, podocin and synaptopodin. Antibodies and staining for nephrin and podocin were reported in a previous publication [7]. The expression of synaptopodin was studied using primary antibodies to synaptopodin (a gift from Dr P. Mundel), followed by incubation with fluorescein isothiocyanate-labelled secondary antibodies, as previously described [7].



   Results
Top
 Abstract
 Introduction
 Materials and methods
 Results
Discussion
 Acknowledgements
 References
 
Human renal tissue experiments
We studied the expression of proteins that localize either to the slit diaphragm (nephrin and podocin) or the cytoskeleton (synaptopodin) in the podocyte foot processes of the renal tissue from seven women who died during the course of preeclampsia. As controls, we examined renal autopsy material of women who died accidentally during otherwise normal pregnancies. We obtained kidney tissue samples that were embedded in paraffin and stored anywhere between 5 and 50 years. The tissue preservation was variable, but in all cases and controls renal sections strongly stained for podocin, indicating that the immunoreactivity of the tissue samples was preserved. All kidney sections were stained initially with haematoxylin and eosin and examined under light microscopy, looking for the presence of the glomerular lesion of endotheliosis, a classic pathological renal lesion of preeclampsia. Once the presence of this lesion (capillary loops occlusion by swelling and hypertrophy of endocapillary cells) was confirmed, the remaining sections were stained for nephrin, podocin and synaptopodin.

Light microscopy showed normal histology in both controls (controls 1 and 2, Table 1). In all cases (cases 1–7, Table 1), florid endotheliosis was present (Figure 1A); this was frequently associated with thrombotic microangiopathy (Figure 1B). In the control kidneys, strong, diffuse capillary wall staining for both nephrin and synaptopodin was present as expected (Figures 2A and 3A, respectively). Expressions of both nephrin (Figure 2B and C) and synaptopodin (Figure 3B and C) were decreased in cases compared with controls; the degree of down-regulation varied from a marked decrease to almost complete absence of protein expression. Podocin did not appear to be affected, as both cases and controls demonstrated strong staining for podocin (Figure 4A and B, respectively). Electron microscopy (Figure 5) showed marked glomerular endotheliosis coupled with segmental foot-process effacement.


Figure 1
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  		Fig. 1. Light microscopy of renal sections from autopsy material of patients with preeclampsia. Florid glomerular endotheliosis (Figure 1A, case 1 from Table 1) was present and frequently associated with thrombotic microangiopathy (Figure 1B, case 3 from Table 1). Haematoxylin and eosin, original magnification 100x.

 

Figure 2
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  		Fig. 2. Immunocytochemistry for nephrin. Uniform, strong staining in controls (Figure 2A, control 1 from Table 1); in cases, nephrin expression was either markedly reduced (Figure 2B, case 3 from Table 1), or absent (Figure 2C, case 2 from Table 1). Magnification 100x, 400x and 200x, respectively.

 

Figure 3
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  		Fig. 3. Immunocytochemistry for synaptopodin. Normal expression is demonstrated in controls (Figure 3A, control 1 from Table 1), 100x with significant down-regulation (Figure 3B, case 5 from Table 1), 200x or complete absence of protein expression (Figure 3C, case 2 from Table 1), and 200x in cases. Magnification 100x, 200x and 200x, respectively.

 

Figure 4
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  		Fig. 4. Immunocytochemistry for podocin. Both controls (Figure 4A, control 1 from Table 1) and cases (Figure 4B, case 7 from Table 1) demonstrated strong, continuous podocin staining. Magnification 200x.

 

Figure 5
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  		Fig. 5. Electron microscopy of kidney sections from a patient who died from severe preeclampsia/HELLP (case 7 from Table 1), showing marked endothelial cell swelling and vacuolization with compromise of capillary loop lumens and extensive epithelial foot-process effacement. Magnification 7400x.

 
Animal experiments
The expressions of nephrin, podocin and synaptopodin were examined in the kidney sections from mice infused with either sFlt-1 (Figure 6A) or anti-VEGF antibodies (Figure 6B) at concentrations corresponding to 10 times the molar concentration of normal plasma VEGF. The expression of nephrin was significantly reduced both with anti-VEGF antibodies and sFlt-1 treatments, and that of podocin was unchanged. Both anti-VEGF antibodies and sFlt-1 significantly reduced the expression of synaptopodin that, similar to nephrin, was restored in rescue experiments when 32.5 pM of VEGF was delivered 5 min after infusion of either anti-VEGF antibodies or sFlt-1.


Figure 6
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  		Fig. 6. Blocking of circulating VEGF reduces the expression of nephrin and synaptopodin, but does not affect podocin. Immunofluorescence staining of kidney sections for nephrin, synaptopodin and podocin, comparing control mice (injected with IgG1) to those receiving 32.5 pM of either s-Flt-1 (Figure 6A) or anti-VEGF antibody (Figure 6B). Rescue experiments with equimolar VEGF treatment restored nephrin and synaptopodin expression in both sFlt-1 and anti-VEGF pre-treated mice.

 


   Discussion
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
Acknowledgements
 References
 
To the best of our knowledge, this is the first study to report that proteinuria in patients with preeclampsia is associated with under-expression of podocyte foot-process proteins, namely nephrin and synaptopodin. Down-regulation of both nephrin and synaptopodin was observed in diagnostically unequivocal cases: all patients had severe forms of preeclampsia, including eclampsia and HELLP syndrome, as indicated by their clinical presentations. In addition, light microscopy of representative kidney sections showed glomerular endotheliosis, a renal lesion, which is characteristic for preeclampsia. Down-regulation of podocyte proteins may not be due merely to pregnancy, as expressions of nephrin and synaptopodin were normal in kidney sections from controls, i.e. women who died accidentally during the second part of otherwise normal pregnancies.

Recent studies have supported the role of low free VEGF levels in preeclampsia that may contribute to the pathogenesis of this condition in a dual fashion by causing (i) endothelial dysfunction and (ii) glomerular epithelial cell dysregulation, leading to the two main clinical findings of preeclampsia, hypertension and proteinuria, respectively (Figure 7). Experiments with normal healthy mice showed that intravenous infusion of sFlt-1 causes glomerular endotheliosis and proteinuria, likely by down-regulation of nephrin [7]. However, a potential role of nephrin dysregulation in the development of proteinuria in human disease remains unknown.


Figure 7
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  		Fig. 7. sFlt-1 hypothesis. Under hypoxic conditions, the placenta in preeclampsia releases sFlt-1 that binds and neutralizes circulating VEGF. Low free VEGF levels contribute to the pathogenesis of preeclampsia in a dual fashion (i) by causing endothelial dysfunction that leads to hypertension and (ii) by down-regulating the slit diaphragm proteins that results in proteinuria.

 
Kidney biopsies are performed rarely in patients with preeclampsia. Therefore, we used renal tissues from women who died from preeclampsia to study the expressions of podocyte proteins that play critical roles in maintaining the normal filtration barrier, namely nephrin, podocin and synaptopodin. We demonstrated that expressions of both nephrin and synaptopodin were decreased markedly in preeclampsia compared with controls. In contrast, expression of podocin was not affected: strong, diffuse capillary staining was present both in cases and controls. Similar results were obtained in experiments in mice injected with either sFlt-1 or anti-VEGF antibodies [7]: expression of nephrin was reduced significantly while that of podocin was unchanged. The expression of synaptopodin was not studied in previous mice experiments. In this study, by using the same animal model, we have demonstrated that, similar to nephrin, synaptopodin expression is significantly decreased, but that it can be rescued by neutralizing anti-VEGF antibodies or sFlt-1 with equimolar VEGF concentrations. Collectively, these results suggest that elevation in sFlt-1 levels, well documented in preeclampsia, indeed may disrupt the slit diaphragm proteins, thus causing proteinuria. A pattern of podocyte protein dysregulation in human kidney sections (i.e. down-regulation of nephrin and synaptopodin with unchanged expression of podocin) was identical to that observed in the animal model of VEGF neutralization by either anti-VEGF antibodies or sFlt-1. The reasons for the different expressions of nephrin and podocin in both the animal sFlt-1 model and the kidney sections from women with preeclampsia remain unclear. These proteins are known to form a signalling complex that is essential for podocyte function and structural integrity [10]. However, a recent study provided evidence indicating that these two proteins may undergo differential regulation [14]. Nephrin Y1193 phosphorylation, mediated by the Src-family member Yes, enhances podocin–nephrin interactions, thereby augmenting nephrin-dependent signalling; reduced nephrin Y1193 phosphorylation promotes ß-Arrestin2-nephrin interactions, which lead to endocytosis of nephrin, but not podocin, and reduced nephrin signalling. Previous studies have suggested that VEGF stimulates Src activity and promotes the Src-mediated phosphorylation [15]. In preeclampsia, it would be particularly intriguing to postulate that low free VEGF levels may down-regulate Src-mediated nephrin phosphorylation. This would favour the formation of ß-Arrestin2-nephrin complexes, leading to nephrin endocytosis, while the expression of podocin may remain unaffected. The effects of VEGF dysregulation on this specific pathway will be the subject of our future research.

After pregnancies complicated by preeclampsia, proteinuria typically resolves by 12 weeks post-partum. Does this imply that down-regulation of the podocyte foot-process proteins is reversible? Indirect evidence suggesting that the process may indeed be reversible comes from studies of HIV-associated nephropathy: treatment strategies that successfully suppressed HIV transcription in podocytes resulted in re-expression of podocyte differentiation markers, including synaptopodin [16]. Conceivably, a dramatic decrease in sFlt-1 levels within 48 h after delivery (due to removal of the placenta, which likely is a source of elevated sFlt-1 levels in preeclampsia) may allow for the gradual re-expression of the podocyte proteins, leading to resolution of proteinuria.

Our study has several limitations. For most of the cases, we did not have a quantitative measurement of proteinuria from a 24 h urine collection that would have allowed studying the correlation and establishing a possible dose-effect relationship between the down-regulation of podocyte proteins and severity of proteinuria. In addition, we had a relatively small sample size and the tissue used was collected as many as 40 years prior to analysis. The concern may be raised that down-regulation of the podocyte proteins may not be reflective of the disease process, but rather caused by non-specific changes related to tissue decomposition. Reasonably well-preserved glomerular structures on light microscopy, as well as normal expressions of synaptopodin and nephrin in kidney sections from controls that, similar to the cases, were analysed years after actual collection, argue against it. Most importantly, the immunoreactivity of the tissues studied was preserved, as evidenced by strong podocin stainings in all cases and controls. Therefore, despite its limitations, our study provides important preliminary evidence that down-regulation of nephrin and synaptopodin is associated with proteinuria in preeclampsia.

Our results raise several important questions that set the stage for future studies. Most importantly, it remains unclear whether down-regulation of nephrin and synaptopodin is a cause or a consequence of proteinuria in preeclampsia. Future experiments with both cultured podocytes and sFlt-1 animal models of preeclampsia may provide a better understanding of the sequence of events and establish cause-effect relationships among elevated sFlt-1 levels, decreased free VEGF levels, down-regulation of podocyte proteins and proteinuria.

In summary, our findings suggest that down-regulation of nephrin and synaptopodin may cause podocyte dysfunction and proteinuria in preeclampsia. Future studies are required to elucidate the intermediate steps and molecular mechanisms by which abnormal VEGF signalling may disrupt the slit diaphragm and cause proteinuria.



   Acknowledgements
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
References
 
We thank Mrs Morea Petersen from the Division of Anatomical Pathology, University of Cape Town for her help in identifying and processing the kidney sections that were used in this study.

Conflict of interest statement. None declared.



   References
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 

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  5. Park C-W, Park JS, Shim S-S, et al. (2005) An elevated maternal plasma, but not amniotic fluid, soluble fms-like tyrosine kinase-1 (sFlt-1) at the time of mid-trimester genetic amniocentesis is a risk factor for preeclampsia. Am J Obstet and Gynecol 193:984–989.[CrossRef][ISI][Medline]
  6. Chaiworapongsa T, Romero R, Espinoza J, et al. (2004) Evidence supporting a role for blockade of the vascular endothelial growth factor system in the pathophysiology of preeclampsia. Young Investigator Award. Am J Obstet and Gynecol 190:1541–1547 discussion 1547–50.[CrossRef][ISI][Medline]
  7. 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]
  8. Kestila M, Lenkkeri U, Mannikko M, et al. (1998) Positionally cloned gene for a novel glomerular protein–nephrin is mutated in congenital nephrotic syndrome. Mol Cell 1:575–582.[CrossRef][ISI][Medline]
  9. Boute N, Gribouval O, Roselli S, et al. (2000) NPHS2, encoding the glomerular protein podocin, is mutated in autosomal recessive steroid-resistant nephrotic syndrome. Nat Genet 24:349–354.[CrossRef][ISI][Medline]
  10. Huber TB, Kottgen M, Schilling B, et al. (2001) T. Interaction with podocin facilitates nephrin signaling. J Biol Chem 276:41543–41546.[Abstract/Free Full Text]
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  13. Sibai BM. (1990) The HELLP syndrome (haemolysis, elevated liver enzymes, and low platelets): much ado about nothing? Am J Obstet and Gynecol 162:311–316.[ISI][Medline]
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  15. Eliceiri BP, Puente XS, Hood JD, et al. (2002) Src-mediated coupling of focal adhesion kinase to integrin {alpha}v{beta}5 in vascular endothelial growth factor signaling 10.1083/jcb.200109079. J Cell Biol 157:149–160.[Abstract/Free Full Text]
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Received for publication: 8. 3.06
Accepted in revised form: 2.11.06


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