Close Relations between Podocyte Injuries and Membranous Proliferative Glomerulonephritis in Autoimmune Murine Models

Abstract

Background: Membranous proliferative glomerulonephritis (MPGN) is a major primary cause of chronic kidney disease (CKD). Podocyte injury is crucial in the pathogenesis of glomerular disease with proteinuria, leading to CKD. To assess podocyte injuries in MPGN, the pathological features of spontaneous murine models were analyzed. Methods: The autoimmune-prone mice strains BXSB/MpJ-Yaa and B6.MRL-(D1Mit202-D1Mit403) were used as the MPGN models, and BXSB/MpJ-Yaa⁺ and C57BL/6 were used as the respective controls. In addition to clinical parameters and glomerular histopathology, the protein and mRNA levels of podocyte functional markers were evaluated as indices for podocyte injuries. The relation between MPGN pathology and podocyte injuries was analyzed by statistical correlation. Results: Both models developed MPGN with albuminuria and elevated serum anti-double-strand DNA (dsDNA) antibody levels. BXSB/MpJ-Yaa and B6.MRL showed severe proliferative lesions with T and B cell infiltrations and membranous lesions with T cell infiltrations, respectively. Foot process effacement and microvillus-like structure formation were observed ultrastructurally in the podocytes of both MPGN models. Furthermore, both MPGN models showed a decrease in immune-positive areas of nephrin, podocin and synaptopodin in the glomerulus, and in the mRNA expression of Nphs1, Nphs2, Synpo, Actn4, Cd2ap, and Podxl in the isolated glomerulus. Significant negative correlations were detected between serum anti-dsDNA antibody levels and glomerular Nphs1 expression, and between urinary albumin-to-creatinine ratio and glomerular expression of Nphs1, Synpo, Actn4, Cd2ap, or Podxl.Conclusion: MPGN models clearly developed podocyte injuries characterized by the decreased expression of podocyte functional markers with altered morphology. These data emphasized the importance of regulation of podocyte injuries in MPGN.

α-Actinin 4 Potentiates Nuclear Factor κ-Light-chain-enhancer of Activated B-cell (NF-κB) Activity in Podocytes Independent of Its Cytoplasmic Actin Binding Function

“…Interestingly, ACTN4 deficiency is also found in multiple human primary glomerulopathies including sporadic FSGS, minimal change disease, and IgA nephropathy (34 -37). Recent studies further indicated that the abundance of ACTN4 protein is significantly reduced in experimental glomerular diseases (38,39). Indeed, Actn4 knock-out mice do not survive the perinatal period, and the remaining mice that survive exhibit severe glomerular defects, podocyte injury, and proteinuria (40).…”

BXSB-type genome causes murine autoimmune glomerulonephritis: pathological correlation between telomeric region of chromosome 1 and Yaa

“…In our previous study, we observed infiltrating B cells in the glomerulus of male BXSB/MpJ-Yaa mice, although they were scarce in the lupus-prone B6.MRLc1 16 and female BXSB/MpJ mice. Therefore, we considered that the Yaa locus contributes to glomerular B-cell infiltration, leading to the severe MPGN in male BXSB/MpJ-Yaa mice.…”

“…20 We previously demonstrated that male BXSB/MpJ-Yaa mice at 3 months of age clearly show MPGN associated with glomerular IC depositions; no lesions were observed in females at the same age. 15,16 Therefore, the pathophysiology of the BXSB/MpJ-Yaa strain has been reported in males but not in females. The present study clarified that female BXSB/MpJ mice clearly develop autoantibody production and MPGN with mild albuminuria characterized by glomerular hypertrophy, increased mesangial cells and their matrix and thickening of GBM at 7 months of age.…”

“…14 We have previously demonstrated that BXSB/MpJ-Yaa mice develop glomerular lesions with decreased functional podocyte proteins, thereby leading to proteinuria subsequent to the formation of tubulointerstitial lesions. 15,16 Interestingly, the C57BL/6-type background congenic strain carrying Yaa does not develop an autoimmune phenotype. 17 These findings indicate that Yaa in a BXSB/MpJ genomic background is associated with the disruption of autoimmunity.…”

Isolation of Glomerular Podocytes by Cationic Colloidal Silica-coated Ferromagnetic Nanoparticles

“…A reduction of the negative membrane charge in the glomerular filter has been observed, e.g., in diabetic nephropathy [28], in the nephrotic stage of IgA nephropathy [29], or in the rat model of puromycin induced nephrosis [30]. Consistent with a reduced negative charge of the podocyte cell surface, the expression of the sialo-and sulfoprotein podocalyxin (PODXL), the major contributor to the anionic surface charge of podocytes [31], respectively of the sialylation of PODXL is decreased in a variety of acquired human kidney diseases [32] and experimental nephropathy models [30,33,34]. To examine if NPs would in principle also be suitable for isolation of podocytes from mice with pathological glomerular alterations, the method was tested using transgenic mice of two established murine nephropathy models: GH-transgenic mice, a model of progressive glomerulosclerosis [35,36], and GIPR dn -transgenic mice, a model of diabetes mellitus associated nephropathy [16].…”