Elsevier

Life Sciences

Volume 79, Issue 8, 17 July 2006, Pages 757-763
Life Sciences

Expression of synaptopodin and GLEPP1 as markers of steroid responsiveness in primary focal segmental glomerulosclerosis

https://doi.org/10.1016/j.lfs.2006.02.031Get rights and content

Abstract

The crucial involvement of podocyte failure in the development of hereditary focal segmental glomerulosclerosis (FSGS) indicates that specific podocyte proteins are closely related to podocyte function and biology. We hypothesized that podocyte failure, reflected by alteration of these proteins, leads not only to FSGS but also to resistance to steroid therapy. We investigated the association between expression of synaptopodin and glomerular epithelial protein 1 (GLEPP1) and response to corticosteroid therapy in primary FSGS. The subjects of this retrospective study were 17 adult patients with primary FSGS with nephrotic syndrome (NS) seen at Fukuoka Red Cross Hospital between 1979 and 2001. They were divided into two groups according to the response to steroid therapy at 6 months: responders (n = 10) and non-responders (persistence of nephrotic-range proteinuria, n = 7). Expression levels of synaptopodin and GLEPP1 were examined immunohistochemically using image analysis software. Low expression levels of both proteins were associated with poor steroid responsiveness in FSGS. The average gray values for synaptopodin and GLEPP1 expression in responders vs. non-responders were 9.0 ± 0.7 (mean ± S.E.M.) vs. 6.3 ± 0.9 (P = 0.04) and 9.6 ± 1.2 vs. 6.0 ± 1.0 (P = 0.04), respectively. The percentages of glomerular area staining for synaptopodin and GLEPP1 in responders vs. non-responders were 15.4 ± 2.7% vs. 8.1 ± 1.2% (P = 0.045) and 11.9 ± 1.6% vs. 6.0 ± 1.3% (P = 0.02), respectively. Synaptopodin expression correlated with the severity of proteinuria and with GLEPP1 expression. Reduced expression of both synaptopodin and GLEPP1 is associated with poor response to steroid therapy in primary FSGS.

Introduction

Primary FSGS is defined clinically by the presence of proteinuria, often in the nephrotic range, and pathologically by segmental glomerular scars involving some but not all glomeruli. Rich first recognized the clinical implications of these lesions in 1957 (Rich, 1957). FSGS is distinguished from minimal change disease (MCD) by hematuria, hypertension, renal insufficiency at presentation, poor response to steroid therapy and a progressive course to end-stage renal disease (ESRD) (Korbet, 2002).

The presence of nephrotic-range proteinuria predicts poor outcome in primary FSGS, with 50% of patients reaching ESRD over 5 to 10 years (Korbet et al., 1986, Rydel et al., 1995). Of all the clinical and histopathological characteristics, only remission of nephrotic-range proteinuria predicts a favorable outcome in nephrotic patients with primary FSGS (Rydel et al., 1995, Pei et al., 1987, Ponticelli et al., 1999, Schwartz et al., 1999). However, no clinical or histopathological features at presentation could predict patients who might enter remission (Pei et al., 1987, Schwartz et al., 1999, Cattran, 1998).

The podocyte is one of the major cell types responsible for maintenance of the glomerular filter. Podocytes also play a crucial role in the maintenance of glomerular structure and their depletion is an important step in the development of FSGS (Pavenstadt et al., 2003). We considered that analysis of podocyte-specific proteins might provide valuable diagnostic and prognostic information for FSGS.

In the present study, we postulated that podocyte failure (characterized by alteration of podocyte-specific proteins) would lead to resistance to therapy as well as glomerular sclerosis. For this purpose, we investigated the expression of synaptopodin and GLEPP1 in primary FSGS by quantification of their expression by computer image analysis. To our knowledge, among several podocyte-specific proteins, only synaptopodin and GLEPP1 are able to be studied immunohistochemically in formalin-fixed, paraffin-embedded tissue for quantifying their expression by computer image analysis.

Synaptopodin is closely associated with the actin microfilament and it is expressed exclusively in the foot process of podocytes in the kidney (Mundel et al., 1997). A decrease or loss of synaptopodin expression was previously observed in idiopathic FSGS (Kemeny et al., 1997, Barisoni et al., 1999, Srivastava et al., 2001). GLEPP1 is a receptor protein tyrosine phosphatase (PTPase) present on the apical cell surface of the glomerular podocyte (Thomas et al., 1994). Sharif et al. (1998) reported that GLEPP1 expression was frequently absent on podocytes, even when no sclerosis was detected in glomeruli of FSGS.

The aim of the present study was to determine the expression levels of synaptopodin and GLEPP1 and their relationship to response to corticosteroid therapy. We also investigated the expression of these proteins in relation to various clinicopathological parameters to investigate whether their expression or podocyte function correlated with these parameters.

Section snippets

Patients

This study was a retrospective clinicopathological analysis of all adult patients (> 15 years old at presentation, n = 2491) with the diagnosis of primary FSGS who were seen at Fukuoka Red Cross Hospital, between 1979 and 2001. Patients with primary FSGS were included in the study if they: (1) had nephrotic syndrome, (2) had been treated with steroid for at least 4 weeks, (3) had a minimum of 1 year of follow-up from the diagnosis of FSGS to ascertain the response to steroid therapy and (4) renal

Patient characteristics

Massive proteinuria was present in 53% of FSGS patients. The average follow-up period for nephrotic patients with FSGS was 3.9 ± 0.4 years (median 3.7).

Response to prednisolone therapy

During the whole period in this study, 11 patients achieved remission, in whom 6 achieved complete remission and 5 achieved partial remission. Ten of these 11 patients entered remission within 6 months of initial therapy and were regarded as responders, while 1 of 11 entered at later than 6 months and was regarded as a non-responder. The time to

Discussion

We investigated the association between synaptopodin and GLEPP1 expression in FSGS and responsiveness to steroid therapy. In this study, reduced expression levels of both synaptopodin and GLEPP1 were observed in the poorly steroid-responsive group in patients with primary FSGS.

FSGS is characterized by focal and segmental glomerular hyalinosis and sclerosis. It responds poorly to steroid treatment and frequently progresses to chronic renal failure (Korbet, 2002). Of all the clinical and

Acknowledgments

We extend special thanks to Ms. H. Noguchi and Mr. M. Munakata for their excellent technical assistance.

References (19)

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