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Kidney Int ; 95(3): 526-539, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30661714

RESUMO

Tubular injury and interstitial fibrosis are the hallmarks of chronic kidney disease. While recent studies have verified that proximal tubular injury triggers interstitial fibrosis, the impact of fibrosis on tubular injury and regeneration remains poorly understood. We generated a novel mouse model expressing diphtheria toxin receptor on renal fibroblasts to allow for the selective disruption of renal fibroblast function. Administration of diphtheria toxin induced upregulation of the tubular injury marker Ngal and caused tubular proliferation in healthy kidneys, whereas administration of diphtheria toxin attenuated tubular regeneration in fibrotic kidneys. Microarray analysis revealed down-regulation of the retinol biosynthesis pathway in diphtheria toxin-treated kidneys. Healthy proximal tubules expressed retinaldehyde dehydrogenase 2 (RALDH2), a rate-limiting enzyme in retinoic acid biosynthesis. After injury, proximal tubules lost RALDH2 expression, whereas renal fibroblasts acquired strong expression of RALDH2 during the transition to myofibroblasts in several models of kidney injury. The retinoic acid receptor (RAR) RARγ was expressed in proximal tubules both with and without injury, and αB-crystallin, the product of an RAR target gene, was strongly expressed in proximal tubules after injury. Furthermore, BMS493, an inverse agonist of RARs, significantly attenuated tubular proliferation in vitro. In human biopsy tissue from patients with IgA nephropathy, detection of RALDH2 in the interstitium correlated with older age and lower kidney function. These results suggest a role of retinoic acid signaling and cross-talk between fibroblasts and tubular epithelial cells during tubular injury and regeneration, and may suggest a beneficial effect of fibrosis in the early response to injury.


Assuntos
Glomerulonefrite por IGA/patologia , Túbulos Renais Proximais/patologia , Miofibroblastos/patologia , Insuficiência Renal Crônica/patologia , Tretinoína/metabolismo , Família Aldeído Desidrogenase 1/metabolismo , Aldeído Oxirredutases/metabolismo , Animais , Benzoatos/farmacologia , Biomarcadores/metabolismo , Biópsia , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Toxina Diftérica/administração & dosagem , Toxina Diftérica/toxicidade , Modelos Animais de Doenças , Células Epiteliais/patologia , Fibrose , Humanos , Túbulos Renais Proximais/citologia , Túbulos Renais Proximais/efeitos dos fármacos , Lipocalina-2/metabolismo , Camundongos , Receptores do Ácido Retinoico/antagonistas & inibidores , Receptores do Ácido Retinoico/metabolismo , Regeneração/efeitos dos fármacos , Insuficiência Renal Crônica/etiologia , Retinal Desidrogenase/metabolismo , Estilbenos/farmacologia , Regulação para Cima , Receptor gama de Ácido Retinoico
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