RESUMEN
Renal interstitial fibrosis is an important mechanism in the progression of chronic kidney disease (CKD) to end-stage kidney disease. However, we lack specific treatments to slow or halt renal fibrosis. Ribosome profiling identified upregulation of a secreted micropeptide, C4orf48 (Cf48), in mouse diabetic nephropathy. Cf48 RNA and protein levels were upregulated in tubular epithelial cells in human and experimental CKD. Serum Cf48 levels were increased in human CKD and correlated with loss of kidney function, increasing CKD stage, and the degree of active interstitial fibrosis. Cf48 overexpression in mice accelerated renal fibrosis, while Cf48 gene deletion or knockdown by antisense oligonucleotides significantly reduced renal fibrosis in CKD models. In vitro, recombinant Cf48 (rCf48) enhanced TGF-ß1-induced fibrotic responses in renal fibroblasts and epithelial cells independently of Smad3 phosphorylation. Cellular uptake of Cf48 and its profibrotic response in fibroblasts operated via the transferrin receptor. RNA immunoprecipitation-sequencing identified Cf48 binding to mRNA of genes involved in the fibrotic response, including Serpine1, Acta2, Ccn2, and Col4a1. rCf48 binds to the 3'UTR of Serpine1 and increases mRNA half-life. We identify the secreted Cf48 micropeptide as a potential enhancer of renal fibrosis that operates as an RNA-binding peptide to promote the production of extracellular matrix.
Asunto(s)
Nefropatías Diabéticas , Fibrosis , Proteínas del Tejido Nervioso , Insuficiencia Renal Crónica , Animales , Humanos , Masculino , Ratones , Regiones no Traducidas 3' , Nefropatías Diabéticas/metabolismo , Nefropatías Diabéticas/patología , Nefropatías Diabéticas/genética , Riñón/metabolismo , Riñón/patología , Ratones Noqueados , Insuficiencia Renal Crónica/metabolismo , Insuficiencia Renal Crónica/patología , Insuficiencia Renal Crónica/genética , Proteínas de Unión al ARN/genética , Proteínas de Unión al ARN/metabolismo , Proteína smad3/metabolismo , Proteína smad3/genética , Factor de Crecimiento Transformador beta1/metabolismo , Factor de Crecimiento Transformador beta1/genética , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/metabolismoRESUMEN
Oxidative stress generating DNA damage has been shown to be a key characteristic in Alzheimer's disease (AD). However, how it affects the pathogenesis of AD is not yet fully understood. Neil3 is a DNA glycosylase initiating repair of oxidative DNA base lesions and with a distinct expression pattern in proliferating cells. In brain, its function has been linked to hippocampal-dependent memory and to induction of neurogenesis after stroke and in prion disease. Here, we generated a novel AD mouse model deficient for Neil3 to study the impact of impaired oxidative base lesion repair on the pathogenesis of AD. Our results demonstrate an age-dependent decrease in amyloid-ß (Aß) plaque deposition in female Neil3-deficient AD mice, whereas no significant difference was observed in male mice. Furthermore, male but not female Neil3-deficient AD mice show reduced neural stem cell proliferation in the adult hippocampus and impaired working memory compared to controls. These effects seem to be independent of DNA repair as both sexes show increased level of oxidative base lesions in the hippocampus upon loss of Neil3. Thus, our findings suggest an age- and sex-dependent role of Neil3 in the progression of AD by altering cerebral Aß accumulation and promoting adult hippocampal neurogenesis to maintain cognitive function.
Asunto(s)
Enfermedad de Alzheimer , ADN Glicosilasas , Masculino , Femenino , Ratones , Animales , Enfermedad de Alzheimer/genética , ADN Glicosilasas/genética , Neurogénesis/genética , Modelos Animales de Enfermedad , Placa Amiloide/genética , Péptidos beta-Amiloides/genética , Trastornos de la MemoriaRESUMEN
Kidney organoids derived from pluripotent stem cells and epithelial organoids derived from adult tissue (tubuloids) have been used to study various kidney disorders with a strong genetic component, such as polycystic kidney disease, Wilms tumor, and congenital nephrotic syndrome. However, complex disorders without clear genetic associations, such as acute kidney injury and many forms of chronic kidney disease, are only just beginning to be investigated using these in vitro approaches. Although organoids are a reductionist model, they contain clinically relevant cell populations that may help to elucidate human-specific pathogenic mechanisms. Thus, organoids may complement animal disease models to accelerate the translation of laboratory proof-of-concept research into clinical practice. This review discusses whether kidney organoids and tubuloids are suitable models for the study of complex human kidney disease and highlights their advantages and limitations compared with monolayer cell culture and animal models.