AP-1 Transcription Factor JunD Confers Protection from Accelerated Nephrotoxic Nephritis and Control Podocyte-Specific Vegfa Expression

Genetic investigation of crescentic glomerulonephritis (Crgn) susceptibility in the Wistar Kyoto rat, a strain uniquely susceptible to nephrotoxic nephritis (NTN), allowed us to positionally clone the activator protein-1 transcription factor Jund as a susceptibility gene associated with Crgn. To study the influence of Jund deficiency (Jund-/-) on immune-mediated renal disease, susceptibility to accelerated NTN was examined in Jund-/- mice and C57BL/6 wild-type (WT) controls. Jund-/- mice showed exacerbated glomerular crescent formation and macrophage infiltration, 10 days after NTN induction. Serum urea levels were also significantly increased in the Jund-/- mice compared with the WT controls. There was no evidence of immune response differences between Jund-/- and WT animals because the quantitative immunofluorescence for sheep and mouse IgG deposition in glomeruli was similar. Because murine Jund was inactivated by replacement with a bacterial LacZ reporter gene, we then investigated its glomerular expression by IHC and found that the Jund promoter is mainly active in Jund-/- podocytes. Furthermore, cultured glomeruli from Jund-/- mice showed relatively increased expression of vascular endothelial growth factor A (Vegfa), Cxcr4, and Cxcl12, well-known HIF target genes. Accordingly, small-interfering RNA–mediated JUND knockdown in conditionally immortalized human podocyte cell lines led to increased VEGFA and HIF1A expression. Our findings suggest that deficiency of Jund may cause increased oxidative stress in podocytes, leading to altered VEGFA expression and subsequent glomerular injury in Crgn

The role of activator FC-gamma receptors in experimental murine glomerulonephritis

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Leptin-Deficient Mice Are Protected from Accelerated Nephrotoxic Nephritis

Leptin is an adipose tissue-derived hormone that signals nutritional status to the hypothalamus. Recent evidence indicates that leptin modifies proinflammatory immune responses and may provide a key link between nutritional deficiency and immune dysfunction. To study the influence of leptin deficiency on immune-mediated renal disease, susceptibility to accelerated nephrotoxic nephritis was examined in leptin-deficient C57BL/6-ob/ob mice and C57BL/6 wild-type controls. The model was induced with sheep anti-mouse glomerular basement membrane antibody injected to mice preimmunized against sheep IgG, and mice were sacrificed 8 days after induction of disease. The leptin-deficient ob/ob mice were strongly protected from glomerular crescent formation, macrophage infiltration, glomerular thrombosis, and albuminuria in this model. Our findings suggest that leptin is required for the induction and maintenance of immune-mediated glomerulonephritis, and that blockade of the leptin axis might provide an attractive therapeutic possibility in human autoimmune disease

Intravenous cyclophosphamide and plasmapheresis in dialysis-dependent ANCA-associated vasculitis

BACKGROUND AND OBJECTIVES: Induction therapy with oral cyclophosphamide (CYP) has been a mainstay of treatment in patients with severe renal failure secondary to ANCA-associated vasculitis (AAV). Recent evidence proposes using pulsed intravenous CYP in less severe disease to minimize adverse events. It is unclear if this can be translated to those with dialysis-dependent renal insufficiency. DESIGN, SETTING, PARTICIPANTS, & METHODS: All AAV patients presenting between 2005 and 2010 requiring dialysis at presentation were retrospectively analyzed. Patients were treated with plasma exchange, corticosteroids, and intravenous CYP. Rate of dialysis independence at 3 and 12 months and adverse effects were assessed and compared with the outcome of the plasmapheresis, prednisolone, and oral CYP arm of the randomized MEPEX (methylprednisolone versus plasma exchange) trial. RESULTS: Forty-one patients were included. At 3 months, 3 (7.3%) patients had died on dialysis, 12 (29.3%) remained dialysis dependent, and 26 (63.4%) were dialysis independent (creatinine, 2.5 mg/dl; GFR, 26 ml/min per 1.73 m(2)). Four patients subsequently reached ESRD at a median time of 83 days. Thirty-seven (90%) patients reached 1 year follow-up, 13 (35%) remained dialysis dependent, and 24 (65%) had independent renal function. Eleven patients (27%) had episodes of leukopenia (white cell count <4×10(9)/L) during CYP therapy and 17 (41%) experienced infectious complications. This compares favorably with the dialysis-dependent cohort treated with plasmapheresis in the MEPEX study in which 51% were alive with independent renal function at 1 year. CONCLUSIONS: Intravenous CYP used with corticosteroids and plasmapheresis may be an effective alternative to oral CYP in patients with dialysis-dependent AAV

Assessing the Validity of an Abdominal CT Scoring System in the Diagnosis of Encapsulating Peritoneal Sclerosis

Background and objectives: Encapsulating peritoneal sclerosis (EPS) is a severe peritoneal fibrotic reaction in patients on long-term peritoneal dialysis (PD). The early clinical features may be nonspecific. The purpose of the study is to assess the reliability and diagnostic utility of abdominal CT scanning in the diagnosis of EPS

Increased incidence of anti-GBM disease in Fcgamma receptor 2b deficient mice, but not mice with conditional deletion of Fcgr2b on either B cells or myeloid cells alone.

Fcgamma receptor 2b (Fcgr2b) is the only inhibitory Fcgamma receptor in both humans and mice, and is implicated in both antibody production and effector responses to antibody complexes. Reduced function of Fcgr2b has previously been associated with anti-glomerular basement membrane antibody (anti-GBM) disease in mice. However, the mice used had 129 genetic elements flanking the deleted Fcgr2b gene, which are known to increase susceptibility to autoimmunity. In order to confirm a role for Fcgr2b in protection from anti-GBM disease, wild type (WT) mice, mice lacking Fcgr2b on a pure C57BL/6 background, or mice lacking Fcgr2b on a C57BL/6 background with 129 flanking sequences, were immunized with the recombinant NC1 domain of alpha 3 Type IV collagen. Twenty two weeks after immunization, there was a higher incidence of crescentic glomerulonephritis, macrophage infiltration and renal dysfunction in both groups of Fcgr2b-/- mice, indicating an important role of Fcgr2b in regulating the development of anti-GBM disease, on both genetic backgrounds. In order to determine the cellular origin of the Fcgr2b-associated effect, disease was induced in mice with deficiency of Fcgr2b on either B cells alone (CD19Cre), or a subset of myeloid cells (LysozymeMCre). Neither B cell nor myeloid specific knockout mice developed crescentic glomeruonephritis with higher incidence than WT mice indicating that Fcgr2b deficiency on either B cells or a subset of myeloid cells alone is not sufficient to increase susceptibility to anti-GBM disease, but that a combination of cell types, or deficiency of Fcgr2b in a different cell type, is also required