Transforming growth factor β3 deficiency promotes defective lipid metabolism and fibrosis in kidney
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 Tgfβ3 deficiency in mice results in early postnatal lethality, we analyzed the kidney phenotype of heterozygous Tgfβ3-knockout mice (Tgfβ3+/-) and compared it with that of matched wild-type mice. Four-month-old Tgfβ3+/- mice exhibited incipient renal fibrosis with epithelial-to-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 showed toxic species such as diacylglycerides and ceramides in Tgfβ3+/- mice, and dysregulated mitochondrial metabolism. Kidney of Tgfβ3+/- mice showed morphological alterations of mitochondria and overactivation of non-canonical MAPK ERK1/2 and JNK cascades. Our study shows that renal TGFβ3 might have antifibrotic and renoprotective properties, opposing or counteracting the activity of TGFβ1.