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Pyelonephritis-Mediated Renal Fibrosis is Associated with Severe Inflammation

ABSTRACT: Despite a growing body of knowledge regarding the pathogenesis of urinary tract infection, the mechanisms of renal scaring associated with acute pyelonephritis (APN) are poorly understood. Limited data available regarding histopathology, immune cell recruitment and gene expression changes during APN severely restricts the development of therapies to prevent renal scars. Here, we address this knowledge gap using inbred, immunocompetent mice with vesicoureteral reflux. Transurethral inoculation of uropathogenic Escherichia coli leads to renal mucosal injury, tubulointerstitial nephritis, and interstitial fibrosis – all histopathologic features of human APN. Interstitial fibrosis correlates most significantly with inflammation 7 and 28 days post infection. Flow cytometry identifies recruitment of neutrophils, macrophages, and lymphocytes to infected kidneys. Renal transcriptional analysis reveals molecular signatures associated with renal ischemia-reperfusion injury, immune cell chemotaxis, and leukocyte activation. Thus, C3H/HeOuJ mice with APN comprise a novel model of renal fibrosis that recapitulates the human condition of acquired renal scarring in an immunocompetent setting. The integration of organ pathology, quantitative cellular immune influx, and transcriptional analyses begin, for the first time, to define mechanisms of tissue injury during APN in the context of an intact immune response. The strong relationship between pro-inflammatory cell recruitment and fibrosis supports the hypothesis that renal scarring arises as a consequence of excessive host inflammation. Our studies suggest that immunomodulatory therapies should be investigated to reduce renal scarring in patients with APN.

ORGANISM(S): Mus musculus

PROVIDER: GSE76469 | GEO | 2016/12/29

SECONDARY ACCESSION(S): PRJNA307537

REPOSITORIES: GEO

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Project description:Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV) are severe inflammatory disorders that often lead to rapid and irreversible organ failure. Rapid progressive glomerulonephritis (RPGN) is a particularly frequent renal manifestation and often leads to extensive glomerular scarring and interstitial fibrosis, resulting in chronic kidney disease and end stage renal failure. Current management options of AAV and its sequelae are limited and common therapies have serious side effects that impair quality of life. A better understanding of the deleterious scarring process of AAV may help to identify novel mechanisms and potential targets for therapy. However, robust murine models of scarring RPGN are still lacking. Here, we present a novel murine model of severe RPGN that recapitulates both acute injury and the subsequent glomerular and interstitial scarring that is based on combined administration of antibodies against the glomerular basement membrane (GBM) and myeloperoxidase (MPO), and bacterial lipopolysaccharides (LPS). Renal injury presented with severe hematuria, glomerular necrosis and crescent formation at 12 days, and consequent glomerular scarring 29 days after initial treatment. We observed increased expression of matrisomal components such as collagens, fibronectin, tenascin-C, in accordance with human AAV as deduced from analysis of gene expression microarray data and tissue staining. Moreover, we observed tissue infiltration by neutrophils, macrophages, T cells and myofibroblasts upon injury. Inhibition of CXCR4 using AMD3100 led to histological and molecular changes in injury with reduced chemokine expression and lower immune cells activation. Using mass-spectrometric proteome analysis, we provide a comprehensive overview of molecular and cellular changes in our AAV model. Altogether, we demonstrate a novel RPGN model that enables the study of matrisomal changes both in disease and upon intervention, as exemplified via CXCR4 inhibition, which could prove to be a viable pharmacological tool and provide matrix as novel targeting opportunity.

Project description:Introduction. Factors contributing to kidney transplant fibrosis remain incompletely understood—particularly in the absence of acute complications. Methods. Baseline and one-year surveillance biopsies from 15 uncomplicated living donor kidney transplants were subjected to microarray and quantitative RT-PCR (qRT-PCR) analyses in order to examine changes in gene expression patterns over time. Biopsy pairs were purposefully selected from allografts with no history of acute complications and were divided into those that were histologically normal (n = 7) and those that had developed subclinical interstitial fibrosis (n = 8) at 1 year. Results. Compared to the paired baseline specimens, expression levels of 3578 probesets were found altered in all the one-year biopsies studied. A large proportion of the upregulated genes in this transplant-associated profile were functionally linked with inflammation, immunity or response to injury. These included components of inflammation-related signaling pathways (integrin, interferon and TLR) as well as individual mediators of inflammatory and immune responses. An additional 2884 probesets demonstrated altered expression in fibrotic grafts only at 1 year. The gene products in this fibrosis-associated profile were also predominantly linked with inflammation and immune function, suggesting exaggerated inflammatory activity within the fibrotic grafts. qRT-PCR analyses confirmed the predicted expression patterns for selected transcripts from the microarray profiles. Conclusions. Transcriptional profiles of histologically normal living donor renal allografts indicate that there is ongoing injury response and inflammation at 1 year compared to the immediate post-transplant period. Subclinical development of interstitial fibrosis during the first post-transplant year is associated with additional upregulation of inflammation-related genes. Keywords: time course, comparative expression We analyzed gene expression from a group of 15 renal transplant patients. All patients had histologically normal time zero biopsy but while 7 remained histologically normal (TxNorm), 8 developed subclinical interstitial fibrosis (GIF/TA) by 1 year. Patient groups were carefully selected to include patients on the same immunosuppresion therapy, transplant type, biopsy histology and absence of overt post-transplant complications (acute rejection, BK, etc). This dataset is part of the TransQST collection.

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Pyelonephritis-Mediated Renal Fibrosis is Associated with Severe Inflammation

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