The podocyte as a direct target of immunosuppressive agents

Eva Schnenberger 1 Jochen H. Ehrich 0 Hermann Haller 1 Mario Schiffer 1 0 Department of Pediatric Nephrology, Hepatology and Metabolic Diseases, Medical School Hannover , 30625 Hannover, Germany 1 Department of Nephrology Podocytes play a key role in maintaining the blood-urine barrier for high-molecular-weight proteins. They are considered to be terminally differentiated, and podocyte loss cannot be compensated by regenerative proliferation. Various diseases leading to podocyte damage and loss result in proteinuria and cause nephrotic syndrome. Therefore, direct therapeutical strategies to protect podocytes in disease situations are a logical concept to prevent disease or to delay disease progression. Acquired podocytopathies like idiopathic focal segmental glomerulosclerosis and minimal change disease are historically considered as immunological diseases. Therefore, immunosuppressive agents such as steroids and calcineurin inhibitors are the commonly used treatment strategies. However, the causative disease mechanisms behind these treatment strategies remain elusive. Recent evidence shows that immunosuppressive agents, in addition to the effect on the immune system, directly influence the unique structure and function of podocytes. In this context, the actin cytoskeleton of the podocyte and cytokines such as vascular endothelial growth factor play a pivotal role. In this review, we summarize the direct effects on podocytes obtained in vivo and in vitro after treatment with calcineurin inhibitors, mTOR inhibitors and glucocorticoids. These direct effects could play a key role in the treatment concepts of podocytopathies with an important impact on the long-term renal function in patients with pharmacological immunosuppression. The Author 2010. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please e-mail: Introduction Nephrotic syndrome is common in adults and is one of the most common kidney diseases in children [1]. The majority of non-genetic nephrotic syndromes are caused by membranous nephropathy or focal segmental glomerulosclerosis (FSGS) in adults and minimal change disease (MCD) in children [1,2]. In all these diseases, the podocyte, which is considered to be terminally differentiated, is the primary target of injury [3]. Recently, a possible autoantigen of idiopathic membranous nephropathy (MN) was identified, and the presence of autoantibodies was documented in 70% of patients with idiopathic MN [4]. However, the different pathophysiologies of idiopathic FSGS and MCD are still ongoing subjects of debate and not fully understood. Podocyte foot process effacement and disruption of the glomerular slit diaphragm are common phenotypes observed in almost all glomerular diseases associated with nephrotic-range proteinuria. The common concepts of podocyte foot process effacement involve dedifferentiation, direct injury of the slit diaphragm or the actin cytoskeleton, and changes in the glomerular basement membrane and podocyte interaction [5]. The resulting loss of glomerular barrier function leads to proteinuria. However, sclerosis and adhesion of the glomerular tuft to the Bowmans capsule are restricted to FSGS and absent in MCD. Persistent proteinuria is a prognostic marker for the progression to end-stage renal disease [6]. Patients presenting with long-term nephrotic-range proteinuria and without partial or complete remission progress to end-stage renal disease over the course of 36 years [7]. Acquired podocytopathies like idiopathic FSGS and MCD are historically considered as immunological diseases [8]. Therefore, immunosuppressive agents such as steroids and calcineurin inhibitors are the commonly used treatment strategies. More than 50% of nephrotic adults and ~ 80% of children respond to an induction therapy with glucocorticoids within a range of a few days to several months, and maintenance treatment with glucocorticoids will prevent relapses [9,10]. The response to corticosteroids is still the best prognostic factor for maintaining renal function in idiopathic nephrotic syndrome, irrespective of the histopathology. In steroid-resistant nephrotic syndromes, several other immunosuppressive agents were successfully used as rescue therapy. After kidney transplantation, proteinuria is highly prevalent and associated with decreased patient and allograft survival irrespectively of the underlying primary renal disease. Depending on the definition, up to 45% of patients develop pathological proteinuria mostly due to recurrent glomerulonephritis, chronic allograft nephropathy, de novo transplant glomerulopathy or acute rejection [11]. Morecomplete understanding of the pathogenesis, the involved target cells and the mechanism of action of glucocorticoids in this context. In many cases of minimal change disease, steroid treatment induces remission and restoration of the slit diaphragm architecture, leading to the term steroidsensitive nephrotic syndrome. These findings in patients with MCD demonstrate the reversibility of proteinuria suggesting that glomerular lesions marked by foot process effacement are reversible. However, in steroid-resistant nephrotic syndromes, several other immunosuppressive agents are necessary to induce remission of disease. Calcineurin inhibitors Calcineurin is a serine/threonine phosphatase that is ubiquitously expressed in all mammalian tissues and tightly regulated by Ca2+/calmodulin [38]. Calcineurin dephosphorylates the nuclear factor of activated T-cell (NFAT) family members, leading to nuclear translocation and activation of early genes of the T-cell-driven immune response, e.g. cytokines as IL-2 and IL-4. The immunosuppressive action of calcineurin inhibitors such as cyclosporin A (CsA) or tacrolimus (FK506) is due to the inhibition of the NFAT signalling in T cells by binding to the cytosolic cyclophilins or FK-binding proteins and subsequently inhibiting the phosphatase activity of calcineurin. Recent evidence supports that the podocyte itself is a target of CsA. Faul et al. analysed the consequence of CsA treatment on the actin cytoskeleton of podocytes [39,40]. Treatment of podocytes with CsA leads to a stabilization of the actin cytoskeleton and stress fibres, while calcineurin mediates dephosphorylation of synaptopodin, an actin-organizing protein in podocytes. By blocking calcineurin, the phosphorylation of synaptopodin promotes binding to the chaperone-like protein 14-3-3. Subsequently, synaptopodin is protected against cathepsin L-mediated cleavage and degradation. Thereby, CsA has a stabilizing effect on the actin cytoskeleton. Moreover, calcineurin is tightly regulated by intracellular calcium levels. The podocyte cell membrane-associated transient potential cation channel 6 (TRPC 6) mediates calcium influx, and gain-of-function mutations are known to be causal for genetic forms of FSGS [41]. High levels of intracellular calcium would lead to an activation of (...truncated)