Podocyte protease activated receptor 1 stimulation in mice produces focal segmental glomerulosclerosis mirroring human disease signaling events.

About 30% of patients who have a kidney transplant with underlying nephrotic syndrome (NS) experience rapid relapse of disease in their new graft. This is speculated to be due to a host-derived circulating factor acting on podocytes, the target cells in the kidney, leading to focal segmental glomerulosclerosis (FSGS). Our previous work suggests that podocyte membrane protease receptor 1 (PAR-1) is activated by a circulating factor in relapsing FSGS. Here, the role of PAR-1 was studied in human podocytes in vitro, and using a mouse model with developmental or inducible expression of podocyte-specific constitutively active PAR-1, and using biopsies from patients with nephrotic syndrome. In vitro podocyte PAR-1 activation caused a pro-migratory phenotype with phosphorylation of the kinase JNK, VASP protein and docking protein Paxillin. This signaling was mirrored in podocytes exposed to patient relapse-derived NS plasma and in patient disease biopsies. Both developmental and inducible activation of transgenic PAR-1 (NPHS2 Cre PAR-1Active+/-) caused early severe nephrotic syndrome, FSGS, kidney failure and, in the developmental model, premature death. We found that the non-selective cation channel protein TRPC6 could be a key modulator of PAR-1 signaling and TRPC6 knockout in our mouse model significantly improved proteinuria and extended lifespan. Thus, our work implicates podocyte PAR-1 activation as a key initiator of human NS circulating factor and that the PAR-1 signaling effects were partly modulated through TRPC6.

Maternal micro-chimeric cells in the multiple sclerosis brain.

Maternal microchimeric cells (MMC) pass across the placenta from a mother to her baby during pregnancy. MMC have been identified in healthy adults, but have been reported to be more frequent and at a higher concentration in individuals with autoimmune diseases. MMC in brain tissue from individuals with autoimmune neurological disease has never previously been explored. The present study aims to identify and quantify MMC in adult human brain from control and multiple sclerosis (MS) affected individuals using fluorescent in situ hybridization (FISH) with a probe for the X and Y chromosomes. Post mortem brain tissue from 6 male MS cases and 6 male control cases were examined. Female cells presumed to be MMC were identified in 5/6 MS cases and 6/6 control cases. Cell specific labeling identified female cells of neuronal and immune phenotype in both control and active MS lesion tissue. This study shows that female cells presumed to be MMC are a common phenomenon in adult human brain where they appear to have embedded into brain tissue with the ability to express tissue specific markers.

Disease-responsive neural precursor cells are present in multiple sclerosis lesions.

AIMS: Spontaneous tissue repair occurs in multiple sclerosis (MS), but the origin of remyelinating cells remains obscure. Here we explore the hypothesis that endogenous neural precursors are involved in MS disease processes. MATERIALS & METHODS: We studied postmortem brain and spinal cord samples from MS patients using immunocytochemical techniques. RESULTS: We show that cells co-positive for nestin and musashi-1 are not merely present in lesions, but found in markedly increased numbers (up to fivefold). Small numbers of nestin-positive cells show direct evidence of proliferation, co-staining for Ki67; some also coexpress glial fibrillary acidic protein or oligodendrocyte progenitor markers (NG-2 or PDGF-alpha receptor), or the early neuronal marker doublecortin, consistent with transition from neural precursors. CONCLUSIONS: These findings suggest that endogenous neural precursors react to disease processes in MS.