Forced expression of laminin β1 in podocytes prevents nephrotic syndrome in mice lacking laminin β2, a model for Pierson syndrome

Abstract

Pierson syndrome is a congenital nephrotic syndrome with ocular and neurological defects caused by mutations in LAMB2 , the gene encoding the basement membrane protein laminin β2 (Lamβ2). It is the kidney glomerular basement membrane (GBM) that is defective in Pierson syndrome, as Lamβ2 is a component of laminin-521 (LM-521; α5β2γ1), the major laminin in the mature GBM. In both Pierson syndrome and the Lamb2 −/− mouse model for this disease, laminin β1 (Lamβ1), a structurally similar homolog of Lamβ2, is marginally increased in the GBM, but it fails to fully compensate for the loss of Lamβ2, leading to the filtration barrier defects and nephrotic syndrome. Here we generated several lines of Lamβ1 transgenic mice and used them to show that podocyte-specific Lamβ1 expression in Lamb2 −/− mice abrogates the development of nephrotic syndrome, correlating with a greatly extended lifespan. In addition, the more Lamβ1 was expressed, the less urinary albumin was excreted. Transgenic Lamβ1 expression increased the level of Lamα5 in the GBM of rescued mice, consistent with the desired increased deposition of laminin-511 (α5β1γ1) trimers. Ultrastructural analysis revealed occasional knob-like subepithelial GBM thickening but intact podocyte foot processes in aged rescued mice. These results suggest the possibility that up-regulation of LAMB1 in podocytes, should it become achievable, would likely lessen the severity of nephrotic syndrome in patients carrying LAMB2 mutations.

RNA-binding protein IGF2BP2/IMP2 is required for laminin-β2 mRNA translation and is modulated by glucose concentration

“…This results in the reduction of LAMB2 synthesis. Because levels of LAMB2 protein are critical to podocyte function (13,23,28,30,43,45), understating mechanisms that modulate LAMB2 protein production provides new, potential therapeutic targets. A primary goal of our work is to apply such work to DN.…”

Integrating Activities of Laminins that Drive Basement Membrane Assembly and Function

“…The GBM in these mice also contains the homologous laminin-b1 subunit and expression of this subunit increases in the absence of the b2 subunit. Forced overexpression of the laminin-b1 subunit in the kidney was found to substantially correct the renal disease, evidence that b1 can compensate for b2 but that this compensation is insufficient in the Pierson syndrome model (Suh, Jarad, VanDeVoorde, & Miner, 2011).…”

Recent advances of animal model of focal segmental glomerulosclerosis

“…Myosin 1e (Myo1e) is one of the two Src homology 3 domain-containing "long-tailed" type I myosins in Actin filament cross-linking protein/Interacts with integrins and strengthens the podocyte-GBM interaction Atypical protein kinase C [68][69][70][71] Tight junctions/Formation of Par complex and interacts with slit diaphragm Rhophilin-1 [80] Rho GTPase activating protein 24 [80] Cytoplasm/Rho GTPase-interacting protein, integrity of glomerular filtration barrier Angiotensin II receptor [55][56][57] Angiotensin-converting enzyme [55][56][57] Membrane/pseudocyst formation at podocyte CD2-associated protein [65][66][67] CD2-associated protein [64] Insertion site of the slit diaphragm/Formation SD complex with podocin and nephrin Laminin subunit beta-2 [81][82][83][84] Laminin subunit beta-2 [81][82][83][84] Podocyte anchoring and differentiation in GBM microRNA 193α [74,75] Cytoplasm/Inhibition of expression of WT-1 Myosin 1e [49,50] Myosin 1e [49,50] Actin binding long-tailed motor protein/Regulation of actin cytoskeleton Nuclear factor of activated T cells [76,77] Transient receptor potential 6 [53,54] Membrane/the activation of calcineurin-NFAT/Wnt signaling via the increased calcium influx Podocin [46] Podocin [58,59] Insertion site of the SD/SD assembly and maintaining the signaling of nephrin Shroom family member 3 …”

“…It is caused by a homozygous or compound heterozygous mutation in the gene encoding laminin beta2 (LAMB2) on chromosome 3p21 [82,83]. This mutation was proved in animal model which showed mesangial sclerosis and highly expressed LMB2 in basement membrane [84] ( Table 2; Fig. 1).…”