ABSTRACT
MicroRNAs (miRNAs) are small, noncoding RNAs that regulate protein levels posttranscriptionally. miRNAs play important regulatory roles in many cellular processes and have been implicated in several diseases. Recent studies have reported significant levels of miRNAs in a variety of body fluids, raising the possibility that miRNAs could serve as useful biomarkers. Here, changes in miRNA expression patterns are described in 2 different rodent models of glomerular injury (acute puromycin aminonucleoside nephropathy and passive Heymann nephritis). By employing 2 different modes of glomerular insult, oxidative stress and immune-mediated toxicity, miRNA changes in both isolated glomeruli as well as urine specimens allow for identification of urinary miRNA biomarkers that are suggestive of drug-induced injury specifically to the glomerulus. Subsets of glomerular urinary miRNAs associated with these different modes of glomerular toxicity seem to be dependent on the mechanism of the induced injury, while 9 miRNAs that changed early in both glomerular and urine specimens were common to both studies. We further show that the miRNAs identified as mechanism-specific early glomerular injury biomarkers target key pathways and transcripts relevant to the type of insult, while the insult-independent changes might serve as ideal glomerular injury biomarkers.
Subject(s)
Acute Kidney Injury/urine , Disease Models, Animal , Glomerulonephritis, Membranous/metabolism , Kidney Glomerulus/metabolism , MicroRNAs/urine , Acute Kidney Injury/metabolism , Acute Kidney Injury/pathology , Acute Kidney Injury/physiopathology , Animals , Biomarkers/metabolism , Biomarkers/urine , Disease Progression , Gene Expression Regulation/drug effects , Glomerulonephritis, Membranous/immunology , Glomerulonephritis, Membranous/pathology , Glomerulonephritis, Membranous/physiopathology , Heymann Nephritis Antigenic Complex/chemistry , Immune Sera/toxicity , Kidney Glomerulus/immunology , Kidney Glomerulus/physiopathology , Kidney Glomerulus/ultrastructure , Laser Capture Microdissection , Male , Metabolomics/methods , MicroRNAs/metabolism , Microscopy, Electron, Transmission , Oxidative Stress/drug effects , Podocytes/drug effects , Podocytes/immunology , Podocytes/metabolism , Podocytes/ultrastructure , Puromycin Aminonucleoside/toxicity , Rats, Sprague-Dawley , Sheep, DomesticABSTRACT
Pancreatic toxicity commonly affects the endocrine or exocrine pancreas. However, it can also occur at the endocrine-exocrine interface (EEI), where the capillary network of the islet merges with the capillaries of the surrounding acinar tissue, that is, the insulo-acinar portal system. The goal of this article is to describe a novel, test article-induced pancreatic toxicity that originated at the EEI and to summarize investigations into the mechanistic basis of the injury. This injury was initially characterized by light microscopy in 7/14 day-toxicity studies in Sprague-Dawley (Crl: CD®[SD]) rats with undisclosed test articles. Microvascular injury at the interface resulted in peri-islet serum exudation, fibrin deposition, hemorrhage, inflammation, and secondary degeneration/necrosis of surrounding exocrine tissue. More chronic injury presented as islet fibrosis and lobular atrophy. Direct cytotoxicity affecting the capillary endothelium at the EEI was confirmed ultrastructurally on day 4. Endothelial microparticle and blood flow studies further confirmed endothelial involvement. Similar lesions occurred less frequently in 2 other rat strains and not in the mouse, dog, or cynomolgus macaque. In summary, in vivo and investigative study data confirmed primary endothelial cytotoxicity in the pathogenesis of this lesion and suggested that the lesion may be rat/rat strain-specific and of uncertain relevance for human safety risk assessment.
