Rapamycin Ameliorates Proteinuria and Restores Nephrin and Podocin Expression in Experimental Membranous Nephropathy

Stavros Stratakis,Rafaela Poulidaki,Spyros Stratigis,Vasiliki Mavroeidi,Eleftheria Vardaki,Ioannis Petrakis,Kostas Stylianou,Christina Petra,Lydia Nakopoulou,Eugene Daphnis,Demitrios Moisiadis

doi:10.1155/2013/941893

Abstract

Objective. Recent studies have shown a beneficial effect of rapamycin in passive and active Heymann Nephritis (HN). However, the mechanisms underlying this beneficial effect have not been elucidated. Methods. Passive Heymann Nephritis (PHN) was induced by a single intravenous infusion of anti-Fx1 in 12 Sprague-Dawley male rats. One week later, six of these rats were commenced on daily treatment with subcutaneous rapamycin 0.5 mgr/kg (PHN-Rapa). The remaining six rats were used as the proteinuric control group (PHN) while six more rats without PHN were given the rapamycin solvent and served as the healthy control group (HC). All rats were sacrificed at the end of the 7th week. Results. Rapamycin significantly reduced proteinuria during the autologous phase of PHN. Histological lesions were markedly improved by rapamycin. Immunofluorescence revealed attenuated deposits of autologous alloantibodies in treated rats. Untreated rats showed decreased glomerular content of both nephrin and podocin whereas rapamycin restored their expression. Conclusions. Rapamycin monotherapy significantly improves proteinuria and histological lesions in experimental membranous nephropathy. This beneficial effect may be mediated by inhibition of the alloimmune response during the autologous phase of PHN and by restoration of the normal expression of the podocyte proteins nephrin and podocin.

Highlights

Membranous nephropathy (MN) is a common cause of nephrotic syndrome (NS), accounting for approximately 20% of cases in Caucasians [1]
In particular we examined the effect of rapamycin on podocytes architecture and slit diaphragm proteins, as well as on the deposition of pathogenic autoantibodies that coincides with the autologous phase of Passive Heymann Nephritis (PHN)
The 24-hour urinary protein of both PHN and PHN-Rapa groups increased at nephrotic levels at day 7 and remained so until the 2nd week after nephritis induction

Summary

Introduction

Membranous nephropathy (MN) is a common cause of nephrotic syndrome (NS), accounting for approximately 20% of cases in Caucasians [1]. The probability of end-stage renal disease (ESRD) in untreated patients is approximately 15% at five years, 35% at 10 years, and 40% at 15 years [2,3,4, 6]. Recent evidence suggests that the majority of patients with idiopathic MN have circulating antibodies against phospholipase A2 receptor (PLA2R), which is present on podocytes, as is megalin in rat models of MN [9]. Neutral endopeptidase has been found as the target antigen in newborns’ podocytes with alloimmune neonatal membranous nephropathy [10] and cationic bovine serum albumin as a planted antigen in early childhood MN [11]. It is speculated that as a result of podocyte injury by complement, various intracellular proteins and cryptic epitopes may be exposed, inducing “a second wave of immunisation” [13, 14]

Methods

Results

Conclusion