RESUMEN
Primary/secondary hyperoxalurias involve nephrocalcinosis-related chronic kidney disease (CKD) leading to end-stage kidney disease. Mechanistically, intrarenal calcium oxalate crystal deposition is thought to elicit inflammation, tubular injury and atrophy, involving the NLRP3 inflammasome. Here, we found that mice deficient in NLRP3 and ASC adaptor protein failed to develop nephrocalcinosis, compromising conclusions on nephrocalcinosis-related CKD. In contrast, hyperoxaluric wild-type mice developed profound nephrocalcinosis. NLRP3 inhibition using the ß-hydroxybutyrate precursor 1,3-butanediol protected such mice from nephrocalcinosis-related CKD. Interestingly, the IL-1 inhibitor anakinra had no such effect, suggesting IL-1-independent functions of NLRP3. NLRP3 inhibition using 1,3-butanediol treatment induced a shift of infiltrating renal macrophages from pro-inflammatory (CD45+F4/80+CD11b+CX3CR1+CD206-) and pro-fibrotic (CD45+F4/80+CD11b+CX3CR1+CD206+TGFß+) to an anti-inflammatory (CD45+F4/80+CD11b+CD206+TGFß-) phenotype, and prevented renal fibrosis. Finally, in vitro studies with primary murine fibroblasts confirmed the non-redundant role of NLRP3 in the TGF-ß signaling pathway for fibroblast activation and proliferation independent of the NLRP3 inflammasome complex formation. Thus, nephrocalcinosis-related CKD involves NLRP3 but not necessarily via intrarenal IL-1 release but rather via other biological functions including TGFR signaling and macrophage polarization. Hence, NLRP3 may be a promising therapeutic target in hyperoxaluria and nephrocalcinosis.
Asunto(s)
Plasticidad de la Célula , Hiperoxaluria/metabolismo , Inflamasomas/metabolismo , Interleucina-1/metabolismo , Riñón/metabolismo , Macrófagos/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Nefrocalcinosis/metabolismo , Insuficiencia Renal Crónica/metabolismo , Animales , Butileno Glicoles/farmacología , Proteínas Adaptadoras de Señalización CARD/genética , Proteínas Adaptadoras de Señalización CARD/metabolismo , Plasticidad de la Célula/efectos de los fármacos , Células Cultivadas , Modelos Animales de Enfermedad , Femenino , Fibroblastos/inmunología , Fibroblastos/metabolismo , Fibroblastos/patología , Hiperoxaluria/tratamiento farmacológico , Hiperoxaluria/inmunología , Hiperoxaluria/patología , Inflamasomas/efectos de los fármacos , Inflamasomas/genética , Inflamasomas/inmunología , Interleucina-1/inmunología , Riñón/inmunología , Riñón/patología , Macrófagos/efectos de los fármacos , Macrófagos/inmunología , Macrófagos/patología , Masculino , Ratones Endogámicos C57BL , Ratones Noqueados , Proteína con Dominio Pirina 3 de la Familia NLR/antagonistas & inhibidores , Proteína con Dominio Pirina 3 de la Familia NLR/genética , Proteína con Dominio Pirina 3 de la Familia NLR/inmunología , Nefrocalcinosis/inmunología , Nefrocalcinosis/patología , Nefrocalcinosis/prevención & control , Fenotipo , Receptores de Factores de Crecimiento Transformadores beta/metabolismo , Insuficiencia Renal Crónica/inmunología , Insuficiencia Renal Crónica/patología , Insuficiencia Renal Crónica/prevención & control , Transducción de SeñalRESUMEN
The characteristics of nonspecific immunity were studied on an outpatient material of 80 non-smoking women aged 38-60 years, with manifestations of hereditary primary enzymopathy (hyperoxaluria syndrome). Hyperoxaluria was shown to be related to immunologic imbalance of some components of nonspecific resistance by the cellular and humoral type. In addition to biochemical differences, the group of patients with prognostically favourable chronic asthmatic bronchitis have got immunologic differences with the alternative group.