Open AccessTransforming growth factor β3 deficiency promotes defective lipid metabolism and fibrosis in murine kidney
Author(s) -
Elia Escasany,
Borja Lanzón,
Almudena García-Carrasco,
Adriana IzquierdoLahuerta,
Lucía Torres,
Patricia Corrales,
Ana Elena Rodríguez-Rodríguez,
Sergio Luis-Lima,
Concepción Martínez Álvarez,
Francisco J. Ruperez,
Manuel Ros,
Esteban Porrini,
Mikael Rydén,
Gema MedinaGómez
Publication year - 2021
Publication title -
disease models and mechanisms
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.327
H-Index - 83
eISSN - 1754-8411
pISSN - 1754-8403
DOI - 10.1242/dmm.048249
Subject(s) - fibrosis , endocrinology , lipid metabolism , medicine , podocyte , transforming growth factor , glomerulosclerosis , biology , kidney , kidney disease , knockout mouse , oxidative stress , proteinuria , receptor
Glomerulosclerosis and tubulointerstitial fibrosis are pathological features of chronic kidney disease. Transforming growth factor β (TGFβ) is a key player in the development of fibrosis. However, of the three known TGFβ isoforms, only TGFβ1 has an established role in fibrosis, and the pathophysiological relevance of TGFβ2 and TGFβ3 is unknown. Because Tgfb3 deficiency in mice results in early postnatal lethality, we analyzed the kidney phenotype of heterozygous Tgfb3-knockout mice (Tgfb3+/-) and compared it with that of matched wild-type mice. Four-month-old Tgfb3+/- mice exhibited incipient renal fibrosis with epithelial-mesenchymal transition, in addition to glomerular basement membrane thickening and podocyte foot process effacement associated with albuminuria. Also evident was insulin resistance and oxidative stress at the renal level, together with aberrant renal lipid metabolism and mitochondrial function. Omics analysis revealed toxic species, such as diacylglycerides and ceramides, and dysregulated mitochondrial metabolism in Tgfb3+/- mice. Kidneys of Tgfb3+/- mice showed morphological alterations of mitochondria and overactivation of non-canonical MAPK ERK1/2 and JNK cascades. Our study indicates that renal TGFβ3 might have antifibrotic and renoprotective properties, opposing or counteracting the activity of TGFβ1. This article has an associated First Person interview with the first author of the paper.