Immunopathogenesis of idiopathic nephrotic syndrome with relapse

Abstract

Idiopathic change nephrotic syndrome (INS), the most frequent glomerular disease in children and young adults, is characterized by heavy proteinuria and a relapsing remitting course. Although the mechanisms underlying the pathophysiology of proteinuria remain unclear, clinical and experimental observations suggest that lymphocyte and podocyte disturbances are two sides of the disease. The current hypothesis suggests that immune cells release a putative factor, which alters podocyte function resulting in nephrotic proteinuria. Besides T-cell abnormalities, recent evidence of B-cell depletion efficacy in sustained remissions added a new challenge in understanding the immunological mechanisms of INS. In this review, we discuss recent insights related to podocyte disorders occurring in INS and their relevance in human diseases.

Figure 1. Structure organization of c-mip

The gene c-mip contains 22 exons spanning 270 Kb. It encodes a messenger RNA of 4.2kb consisting of 434 bp-5′UTR, 2,200 bp -coding sequence and 1600 bp-3′UTR. The protein c-mip is original in that it contains two domains usually not found within the same protein, the Pleckstrin-homogy domain (PH) and LRR domain, as well as an SH3-like domain and many docking sites for signaling molecules.

Figure 2. Current understanding of nephrin signaling

In basal conditions, clustering of nephrin in lipid rafts induces Fyn phosphorylation at tyrosine 417, leading to its conformational change in active form. The amount of active Fyn is amplified upon its interaction with Nck. Then, Fyn phosphorylates nephrin at multiple residues within the cytoplasmic domain, which subsequently recruits several proteins including podocin, CD2AP and synaptopodin. Fyn binds to and phosphorylates N-Wasp. These diverse interactions initiated by Fyn preserve cytoskeleton organization. Phosphorylation of nephrin induces the recruitment of PI3 kinase, which then activates Akt and promotes podocyte survival through activation of NF-κB and WT1. The expression of c-mip is barely detected in physiological conditions. However, in some pathological situations, c-mip abundance is increased and interferes with Fyn activity and nephrin (and likely other podocyte receptors) signaling.

Figure 3. Cross-talk c-mip/NF-κB in anti-VEGF-mediated glomerular diseases

Thrombotic microangiopathy (TMA) is a frequent complication of anti-VEGF ligand therapy (Bevacizumab and VEGF trap), whereas minimal change nephropathy/focal segmental glomerulosclerosis (MCN/FSG) are mostly observed following receptor tyrosine kinase inhibitor (RTKI) treatment. Glomerular TMA is associated with an upregulation of NF-κB that is a strong repressor of c-mip. By contrast, RTKI such as Sorafenib inhibits NF-κB leading to increased c-mip abundance and cytoskeleton disorganization, which subsequently induces nephrotic proteinuria with MCN/FSG-like histological lesions.