Pathogenesis and therapy of focal segmental glomerulosclerosis: an update

Abstract

Focal and segmental glomerulosclerosis (FSGS) is an important cause of steroid-resistant nephrotic syndrome in adults and children. It is responsible for 5-20% of all cases of end-stage kidney disease (ESKD) in the United States. The pathogenesis of FSGS has not been fully elucidated; however, data from molecular studies of familial cases in the last two decades suggest that FSGS is a defect of the podocyte. The therapeutic agents available for treatment of FSGS are not very effective and only a small percentage of affected individuals will achieve complete remission. Recent data from molecular biology and molecular genetics has provided insight into the mechanisms of action of old agents and also identification of other novel therapeutic targets. This review focuses on recent advances in the molecular pathogenesis of FSGS and currently available therapeutic agents as well as potential novel therapies.

Figure 1. The podocyte and the other components of the glomerular filtration barrier

The glomerular filtration barrier is formed by fenestrated endothelial cells, the glomerular basement membrane and podocytes. The podocyte has a unique actin cytoskeleton made up of F-actin and non-muscle myosin such as MYH9. In addition, it has actin-binding proteins such as synaptopodin and α-actinin4 (ACTN4) and actin polymerization regulatory protein inverted formin 2 (INF2). Mutations in ACTN4, INF2 genes are causes of familial FSGS and MYH9 is a complex disease locus in idiopathic FSGS. Wilms’ tumor 1 (WT1) gene is a nuclear transcription factor that is expressed abundantly in the podocyte, mutations in WT1 is a cause of syndromic and non-syndromic nephrotic syndrome. The junctional part of the podocyte (the slit diaphragm) is formed by nephrin, podocin, CD2 aasociated protein (CD2AP) and NEPH1. Podocin associates with lipid rafts, a signaling domain of the slit diaphragm. It recruits nephrin and NEPH1 to form a signaling complex with other molecules such as Transient Receptor Potential Cation Channel, Type 6 (TRPC6), growth factor receptor-bound protein 2 (Grb2) and Phospholipase C epsilon-1 (PLCE1) at the slit diaphragm. Mutations in nephrin, podocin, TRPC6, PLCE1 and CD2AP are known causes of hereditary FSGS and nephrotic syndrome in humans. The apical membrane of the podocyte is formed by negatively charged molecules such as podocalyxin, podoplanin, podoendin and glomerular epithelial protein-1 (GLEPP-1). The basal part of the podocyte contains α3β1 integrin and α and β dystroglycans that anchors the podocyte to the glomerular basement membrane (GBM). Talin, Paxillin and Vincullin (TPV) interact with different laminins in the GBM especially laminin β2. Mutations in laminin β2 is a cause of early onset nephrotic syndrome.

Figure 2. New insight into mechanisms of action of FSGS therapy and novel therapeutic targets

1. In addition to their immunomodulatory role, corticosteroids may also ameliorate kidney injury by increasing actin (A) polymerization through GTPase RhoA [83] 2. Anti-proteinuric effects of calcineurin inhibitors may be as a result of inhibition of dephosphorylation of synaptopodin (S) [85] 3. Inhibition of TRPC6 (T) channel may be useful in the therapy of familial and idiopathic FSGS [46, 52] 4. Galactose may block the binding site or change the configuration of the free soluble factor preventing it from binding to the podocytes [103] 5. Phosphorylation of nephrin (N) and Neph-1 (N1) by Fyn kinase may induce actin polymerization [105, 106]. Modulation of this pathway may be of therapeutic benefit in proteinuric kidney disease. 6. Modulation of sialylation pathway is a potential therapeutic target because glomerular proteinuria induced by mutation in key enzyme of sialic acid synthesis (pathway responsible for sialylation of major podocyte protein such as podocalyxin [P]) is rescued by N-acetylmannosamine [105, 107].

Figure 3. Glomerular parietal epithelial cells (GPEC) as podocyte “stem cells”

A schematic representation of the glomerulus showing the visceral glomerular epithelial cell or podocyte (Pod; blue) and glomerular parietal epithelial cells (PEC; red). Note that PEC and Pod are in direct continuity at the vascular pole (VP). There are three populations of PEC cells, the least differentiated cells (CD133+, podocyte marker (PM−) and CD24+) are found closer to the urine or tubular pole (TP) and the terminally differentiated cells (CD133−, CD24−, PM+) are found at the VP, and intermediate plueripotent cells (CD133+, CD24+, PM+) cells are found midway between the TP and the VP. Injection of CD133+, CD24+ and PM− cells ameliorate the clinical course of adriamycin-induced proteinuria [110]. Adapted and reproduced with permission from Appel et al. [111].