Dataset Information

An atypical parvovirus driving chronic tubulointerstitial nephropathy and kidney fibrosis

ABSTRACT: The occurrence of a spontaneous nephropathy in laboratory mice, characterized by tubular degeneration and intranuclear inclusions, has puzzled pathologists for over four decades. While the condition takes a more severe course in immunodeficient animals suggesting an infectious cause, its etiology has remained elusive. Using an unbiased metagenomics approach, we have identified the causative agent as a novel virus, mouse kidney parvovirus (MKPV), belonging to a divergent and unclassified genus of the Parvoviridae. MKPV was found to be present in animal facilities in Australia and North America, is transmitted via the orofecal route and is controlled by the adaptive immune system. Detailed analysis of the clinical course and histopathologic features demonstrated a stepwise progression of pathology ranging from sporadic tubular inclusions to extensive tubular degeneration and interstitial fibrosis culminating in renal failure. In summary, we identify a novel, widely distributed pathogen in laboratory mice causing significant impact on the interpretation and outcome of biomedical research based on mouse models. Additionally, we establish MKPV-induced nephropathy as a new tool for elucidating the mechanisms of tubulointerstitial fibrosis that shares molecular features with chronic kidney disease in humans.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Kidney

SUBMITTER: Matthew O'Rourke

LAB HEAD: Ben Roediger

PROVIDER: PXD010540 | Pride | 2018-09-06

REPOSITORIES: Pride

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An Atypical Parvovirus Drives Chronic Tubulointerstitial Nephropathy and Kidney Fibrosis.

Roediger Ben B Lee Quintin Q Tikoo Shweta S Cobbin Joanna C A JCA Henderson James M JM Jormakka Mika M O'Rourke Matthew B MB Padula Matthew P MP Pinello Natalia N Henry Marisa M Wynne Maria M Santagostino Sara F SF Brayton Cory F CF Rasmussen Lorna L Lisowski Leszek L Tay Szun S SS Harris David C DC Bertram John F JF Dowling John P JP Bertolino Patrick P Lai Jack H JH Wu Wengen W Bachovchin William W WW Wong Justin J-L JJ Gorrell Mark D MD Shaban Babak B Holmes Edward C EC Jolly Christopher J CJ Monette Sébastien S Weninger Wolfgang W

Cell 20180913 2

The occurrence of a spontaneous nephropathy with intranuclear inclusions in laboratory mice has puzzled pathologists for over 4 decades, because its etiology remains elusive. The condition is more severe in immunodeficient animals, suggesting an infectious cause. Using metagenomics, we identify the causative agent as an atypical virus, termed "mouse kidney parvovirus" (MKPV), belonging to a divergent genus of Parvoviridae. MKPV was identified in animal facilities in Australia and North America, ...[more]

PMID: 30220458

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Project description:Proteinuria is the most important predictor of outcome in glomerulonephritis and experimental data suggest that the tubular cell response to proteinuria is an important determinant of progressive fibrosis in the kidney. However, it is unclear whether proteinuria is a marker of disease severity or has a direct effect on tubular cells in the kidneys of patients with glomerulonephritis. Accordingly we studied an in vitro model of proteinuria, and identified 231 albumin-regulated genes differentially expressed by primary human kidney tubular epithelial cells exposed to albumin. We translated these findings to human disease by studying mRNA levels of these genes in the tubulo-interstitial compartment of kidney biopsies from patients with IgA nephropathy using microarrays. Biopsies from patients with IgAN (n=25) could be distinguished from those of control subjects (n=6) based solely upon the expression of these 231 albumin-regulated genes. The expression of an 11-transcript subset related to the degree of proteinuria, and this 11-mRNA subset was also sufficient to distinguish biopsies of subjects with IgAN from control biopsies. We tested if these findings could be extrapolated to other proteinuric diseases beyond IgAN and found that the all forms of primary glomerulonephritis (n=33) can be distinguished from controls (n=21) based solely on the expression levels of these 11 genes derived from our in vitro proteinuria model. Pathway analysis suggests common regulatory elements shared by these 11 transcripts. In conclusion, we have identified an albumin-regulated 11-gene signature shared between all forms of primary glomerulonephritis. Our findings support the hypothesis that albuminuria may directly promote injury in the tubulo-interstitial compartment of the kidney in patients with glomerulonephritis. We used microarrays to analyze the transcriptome of microdissected renal biopsies from patients with IgA nephropathy (IgAN) RNA from tubulointerstitial compartments was extracted and processed for hybridization on Affymetrix HG-U133A microarrays.

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