Asunto(s)
Envejecimiento , Gerociencia , Proteínas Klotho , Memoria , Animales , Humanos , Envejecimiento/efectos de los fármacos , Cognición/efectos de los fármacos , Haplorrinos/fisiología , Inyecciones , Proteínas Klotho/administración & dosificación , Proteínas Klotho/uso terapéutico , Memoria/efectos de los fármacos , Modelos AnimalesRESUMEN
Contrast-induced acute kidney injury (CI-AKI) is a main cause of hospital-acquired renal failure. Nevertheless, limited measures have been shown to be effective for the treatment of CI-AKI. Here, we demonstrated that αKlotho, which is highly expressed in kidney, has therapeutic activity in CI-AKI. Our data showed that αKlotho expression levels were decreased both in the kidney and serum of CI-AKI mice. Administration of αKlotho protein protected the kidney and HK-2 cells against contrast-induced injury. Mechanistically, αKlotho reduced contrast-induced renal tubular cells pyroptosis by limiting NLRP3 inflammasome activation. Meanwhile, αKlotho up-regulated autophagy via inhibiting the AKT/mTOR pathway and decreased mitochondrial ROS level. Inhibition of autophagy blunted the suppression effect of αKlotho on NLRP3 inflammasome activation and cell pyroptosis in contrast-treated HK-2 cells. Taken together, our data suggest that αKlotho protein protects against CI-AKI through inhibiting NLRP3 inflammasome-mediated pyroptosis, which is likely by promoting autophagy. αKlotho may be a promising therapeutic strategy for CI-AKI.
Asunto(s)
Lesión Renal Aguda/tratamiento farmacológico , Inflamasomas/metabolismo , Proteínas Klotho/uso terapéutico , Sustancias Protectoras/uso terapéutico , Piroptosis/efectos de los fármacos , Lesión Renal Aguda/inducido químicamente , Lesión Renal Aguda/metabolismo , Animales , Autofagia/efectos de los fármacos , Medios de Contraste/efectos adversos , Proteínas Klotho/administración & dosificación , Masculino , Ratones Endogámicos C57BL , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Sustancias Protectoras/administración & dosificaciónRESUMEN
Chronic kidney disease (CKD) has a high prevalence worldwide and is an intricate issue to whole medical society. Renal fibrosis is the common pathological feature for various kinds of CKD. As an anti-aging protein, Klotho is predominantly expressed in renal tubular epithelial cells. Reports show Klotho could retard age-related renal fibrosis. Mitochondrial dysfunction plays an important role in cellular senescence. However, the role of Klotho in mitochondrial dysfunction in CKD has not yet been determined. In this study, we treated unilateral ischemia-reperfusion (UIRI) mice and cultured human renal tubular epithelial cells (HKC-8) with Klotho. We assessed renal fibrosis, cellular senescence, and Wnt/ß-catenin signaling. We also focused on mitochondrial function assessment. In UIRI mice, ectopic expression of Klotho greatly retarded fibrotic lesions and the activation of Wnt/ß-catenin signaling. Interestingly, Klotho significantly preserved mitochondrial mass, inhibited mitochondrial reactive oxygen species (ROS) production and restored the expression of mitochondrial respiration chain complex subunits. Consequently, Klotho restrained cellular senescence. In HKC-8 cells, Klotho significantly inhibited Wnt1- and Wnt9a-induced mitochondrial injury, cellular senescence, and fibrotic lesions. These results suggest Klotho has a protective role in renal function through targeted protection on mitochondria. This further broads the understanding of the beneficial efficacies of Klotho in CKD.