RESUMEN

Abnormal renin-angiotensin system (RAS) activation plays a critical role in the initiation and progression of chronic kidney disease (CKD) by directly mediating renal tubular cell apoptosis. Our previous study showed that necroptosis may play a more important role than apoptosis in mediating renal tubular cell loss in chronic renal injury rats, but the mechanism involved remains unknown. Here, we investigate whether blocking the angiotensin II type 1 receptor (AT1R) and/or angiotensin II type 2 receptor (AT2R) beneficially alleviates renal tubular cell necroptosis and chronic kidney injury. In an angiotensin II (Ang II)-induced renal injury mouse model, we found that blocking AT1R and AT2R effectively mitigates Ang II-induced increases in necroptotic tubular epithelial cell percentages, necroptosis-related RIP3 and MLKL protein expression, serum creatinine and blood urea nitrogen levels, and tubular damage scores. Furthermore, inhibition of AT1R and AT2R diminishes Ang II-induced necroptosis in HK-2 cells and the AT2 agonist CGP42112A increases the percentage of necroptotic HK-2 cells. In addition, the current study also demonstrates that Losartan and PD123319 effectively mitigated the Ang II-induced increases in Fas and FasL signaling molecule expression. Importantly, disruption of FasL significantly suppressed Ang II-induced increases in necroptotic HK-2 cell percentages, and necroptosis-related proteins. These results suggest that Fas and FasL, as subsequent signaling molecules of AT1R and AT2R, might involve in Ang II-induced necroptosis. Taken together, our results suggest that Ang II-induced necroptosis of renal tubular cell might be involved both AT1R and AT2R and the subsequent expression of Fas, FasL signaling. Thus, AT1R and AT2R might function as critical mediators.

Asunto(s)

Células Epiteliales/patología , Fallo Renal Crónico/patología , Túbulos Renales/patología , Receptor de Angiotensina Tipo 1/metabolismo , Receptor de Angiotensina Tipo 2/metabolismo , Angiotensina II/administración & dosificación , Angiotensina II/toxicidad , Bloqueadores del Receptor Tipo 1 de Angiotensina II/administración & dosificación , Bloqueadores del Receptor Tipo 2 de Angiotensina II/administración & dosificación , Animales , Línea Celular , Modelos Animales de Enfermedad , Humanos , Imidazoles/administración & dosificación , Fallo Renal Crónico/inducido químicamente , Túbulos Renales/citología , Losartán/administración & dosificación , Masculino , Ratones , Necroptosis/efectos de los fármacos , Oligopéptidos/administración & dosificación , Piridinas/administración & dosificación , Receptor de Angiotensina Tipo 2/agonistas , Transducción de Señal/efectos de los fármacos

RESUMEN

We have developed a unique approach for enhancing the sensitivity of pyrenyl probes based on polyelectrolyte-induced nanoassemblies and explored its sensing application toward 2,4,6-trinitrophenol (TNP). The key issue of the method is the formation of the nanoassemblies which possess high-density charges, specific surface area, and inner hydrophobic regions. These properties would help increase the loading of analytes and promote probe-analyte interactions, thereby leading to the prominent enhancement of the sensitivity. In the course of TNP detection, pyrene nanoassemblies can bind TNP efficiently through cooperative noncovalent interactions including electrostatic, π-π stacking, and charge-transfer interactions, resulting in the distinct fluorescent responses of pyrene moieties. This system has excellent selectivity and sensitivity for TNP detection. The detection limit is as low as 5 nM. It may be used for monitoring the TNP concentrations in real-world samples.