RESUMO
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.
Assuntos
Injúria Renal Aguda/urina , Modelos Animais de Doenças , Glomerulonefrite Membranosa/metabolismo , Glomérulos Renais/metabolismo , MicroRNAs/urina , Injúria Renal Aguda/metabolismo , Injúria Renal Aguda/patologia , Injúria Renal Aguda/fisiopatologia , Animais , Biomarcadores/metabolismo , Biomarcadores/urina , Progressão da Doença , Regulação da Expressão Gênica/efeitos dos fármacos , Glomerulonefrite Membranosa/imunologia , Glomerulonefrite Membranosa/patologia , Glomerulonefrite Membranosa/fisiopatologia , Complexo Antigênico da Nefrite de Heymann/química , Soros Imunes/toxicidade , Glomérulos Renais/imunologia , Glomérulos Renais/fisiopatologia , Glomérulos Renais/ultraestrutura , Microdissecção e Captura a Laser , Masculino , Metabolômica/métodos , MicroRNAs/metabolismo , Microscopia Eletrônica de Transmissão , Estresse Oxidativo/efeitos dos fármacos , Podócitos/efeitos dos fármacos , Podócitos/imunologia , Podócitos/metabolismo , Podócitos/ultraestrutura , Puromicina Aminonucleosídeo/toxicidade , Ratos Sprague-Dawley , Carneiro DomésticoRESUMO
Interactions between PD-1 and its two differentially expressed ligands, PD-L1 and PD-L2, attenuate T cell activation and effector function. To determine the role of these molecules in autoimmune disease of the CNS, PD-1-/-, PD-L1-/- and PD-L2-/- mice were generated and immunized to induce experimental autoimmune encephalomyelitis (EAE). PD-1-/- and PD-L1-/- mice developed more severe EAE than wild type and PD-L2-/- mice. Consistent with this, PD-1-/- and PD-L1-/- cells produced elevated levels of the pro-inflammatory cytokines IFN-gamma, TNF, IL-6 and IL-17. These results demonstrate that interactions between PD-1/PD-L1, but not PD-1/PDL-2, are crucial in attenuating T cell responses in EAE.
