<i>Background:</i> In proteinuria of glomerular origin there is upregulation of heme-oxygenase (HO), the rate-limiting enzyme of heme degradation, in the nephron in a segment-specific manner. To better characterize this phenomenon, we employed a model of proteinuria resulting from disruption of the glomerular capillary permeability barrier to protein by administration of the glomerular epithelial cell toxin puromycin aminonucleoside (PAN) to rats. In this model, we assessed nephron distribution of the expression of the inducible HO isoform, HO-1, and the role of free radicals in modulating HO-1 expression. <i>Methods:</i> Rats were injected with either vehicle (dimethyl sulfoxide) or PAN or the spin trap free radical stabilizer α-phenyl-N-<i>tert</i> butyl nitrone (PBN), or with both PAN and PBN. Ten days following the PAN injection, urine protein, creatinine, nitric oxide (NO) and malonyldialdehyde (MDA) were measured. Kidney sections and protein lysates were assessed for changes in HO-1 expression by immunohistochemistry and Western blot analysis. <i>Results:</i> In control animals (DMSO or PBN alone) there was no proteinuria and very weak or absent HO-1 staining in nephron segments. PAN treatment induced proteinuria and increased urine MDA excretion. In these animals, there was a robust HO-1 expression mainly in tubules and in glomerular parietal but not visceral epithelial cells. Unilateral ureteral obstruction to interrupt glomerular filtration in animals treated with PAN abrogated tubular HO-1 expression in the kidney ipsilateral to the obstruction. Administration of PBN to PAN-treated animals reduced proteinuria and MDA excretion while it markedly augmented tubular HO-1 expression. This augmentation was prominent in tubular cells of the inner cortex/outer medulla. <i>Conclusions:</i> These observations indicate that upregulation of nephron HO-1 following disruption of the glomerular permeability barrier occurs at sites downstream of this barrier and is mediated by a filtered HO-1 inducer(s). Scavenging of free radicals potentiates the effect of this inducer and unmasks nephron segments most and least capable of upregulating HO-1.
Immunosuppressive medications have impacted the course of acute and chronic rejection; however, immunosuppressive drugs have not had any substantial effect on the development of recurrent and de novo disease. Recurrent and de novo diseases after renal transplantation are becoming an increasing problem and are associated with poor transplant outcome. The prevention and management of recurrent and de novo diseases are limited by poor understanding of the pathogenesis of the specific diseases. Consequently, it is important to understand the pathogenesis of each disease and make this knowledge useful in the management of recurrent disease. This review focuses on the recent progress that has been made in understanding the pathogenesis and management options of recurrent disease.
CLCF1 is a neurotrophic and B cell-stimulating factor belonging to the IL-6 family. Mutations in the gene coding for CLCF1 or its secretion partner CRLF1 lead to the development of severe phenotypes, suggesting important nonredundant roles in development, metabolism, and immunity. Although CLCF1 was shown to promote the proliferation of the myeloid cell line M1, its roles on myeloid activation remain underinvestigated. We characterized the effects of CLCF1 on myeloid cells with a focus on monocyte-macrophage and macrophage-foam cell differentiations. CLCF1 injections in mice resulted in a significant increase in CD11b+ circulating cells, including proinflammatory monocytes. Furthermore, CLCF1 activated STAT3 phosphorylation in bone marrow CD11b+ cells and in bone marrow-derived macrophages (BMDM). BMDM stimulated with CLCF1 produced a large array of proinflammatory factors comprising IL-6, IL-9, G-CSF, GM-CSF, IL-1β, IL-12, CCL5, and CX3CL1. The pattern of cytokines and chemokines released by CLCF1-treated BMDM led us to investigate the role of CLCF1 in foam cell formation. When pretreated with CLCF1, BMDM presented a marked SR-A1 upregulation, an increase in acetylated-low-density lipoprotein uptake, and an elevated triglyceride accumulation. CLCF1-induced SR-A1 upregulation, triglyceride accumulation, and acetylated-low-density lipoprotein uptake could be prevented using ruxolitinib, a JAK inhibitor, indicating that the effects of the cytokine on myeloid cells result from activation of the canonical JAK/STAT signaling pathway. Our data reveal novel biological roles for CLCF1 in the control of myeloid function and identify this cytokine as a strong inducer of macrophage-foam cell transition, thus bringing forward a new potential therapeutic target for atherosclerosis.
Objective: To evaluate the relative distribution of service connection disability ratings among veterans with a diagnosis of Posttraumatic Stress Disorder (PTSD) and/or Traumatic Brain Injury (TBI) from all branches of service who went to war before and after a historic attack on US by a terrorist group on September 11, 2001 (9/11); and to determine the associated cost to the nation.Methods: The Veterans Health Administration (VHA) provides care to veterans at over 1,400 medical establishments across the United States. We used clinical data from these establishments, provided by researching the Veterans Administrations Informatics and Computing Infrastructure (VINCI). First, we identified all veterans with the ICD-9 code diagnosis of PTSD and/or TBI who received services within the VA between years 1998 to 2014. We excluded those who had no listed service connection disability rating. The remaining cohort was divided into four groups based on their period of service: Pre-9/11 Group – those who entered and left service before September 11, 2001; Post–9/11 Group– those who first entered the service after September 11, 2001; Overlap-9/11 Group – those who entered service before 2001 and left service after September 11, 2001; Reentered Post-9/11 Group – those who entered and then left service before September 11, 2001 and then reentered after September 11, 2001. Both annual and projected 50-year compensation costs were calculated for these groups.Results: We identified 1,067,691 veterans with PTSD and/or TBI diagnosis who were service connected during the period under study. The relative distribution was highest in Pre-9/11 Group (N=797,285; 74.7%), followed by Post-9/11 Group (N=174,134; 16.3%), Overlap-9/11 Group (N=82,450; 7.7%) and Reentered Post-9/11 Group (N=13,822; 1.3%). Majority of veterans in all groups were male. Veterans in Pre-9/11 Group were oldest (66.3 ± 11.3), those in the Post-9/11 Group were the youngest (36.1 ± 8.7), with the Overlap-9/11 Group (41.2 ± 8.4) and the Reentered Post-9/11 Group (46.7 ± 8.9) showing intermediate average ages. The projected service connection disability compensation cost will be at least $20.28 billion/year and total $515 billion in coming 50 years. Based on the 2014 numbers, we project inpatient and outpatient costs to be $3.63 billion and $1.48 billion annually, and this represents $106.4 billion and 40.4 billion in over the next 50 years, respectively.Conclusions: PTSD/TBI continues to be a devastating problem for veterans, their families, and our society. Rising costs and limited success with currently mandated therapies calls for a new therapeutic approach to help manage this unsustainable cost to the nation.
