Transforming growth factor β3 deficiency promotes defective lipid metabolism and fibrosis in murine kidney

Abstract

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.

The Effects of Sunitinib in Healthy and Cisplatin‐Induced Rats

“…A recent study reported that TGF-β3 may have antifibrotic and renoprotective properties; thus, it maintains renal homeostasis by inhibiting TGFβ1 activity. [30] However, Yu et al [31] reported that all TGF isoforms, including TGF-β3, have fibrogenic effects in renal cells, and the blockade of these isoforms will have a good therapeutic effect in reducing renal fibrosis. Another study noted that the expression level of TGF-β3 decreased in parallel with the improvement in kidney fibrosis.…”

“…In the literature, unlike other TGF isoforms (TGF‐β1 and TGF‐β2), information about TGF‐β3 is very limited and controversial. A recent study reported that TGF‐β3 may have antifibrotic and renoprotective properties; thus, it maintains renal homeostasis by inhibiting TGFβ1 activity [30] . However, Yu et al [31] .…”

Screening and identification of key biomarkers in diabetic kidney disease and its complications: Evidence from bioinformatics and next generation sequencing data analysis

“…In the current investigation, integrated bioinformatics methods assisted in an analysis of how key genes change in their expression to uncover potential DKD based on NGS dataset (GSE217709), and we identified total 958 DEGs, including 479 up regulated genes and 479 down regulated genes. [115], FGFR2 [116], ROR2 [117], RTN1 [118], NOTCH3 [119], JAK3 [120], IL18 [121], COL4A1 [122], CEBPD (CCAAT enhancer binding protein delta) [123], KIF26B [124], HES1 [125], CBS (cystathionine beta-synthase) [126], EGF (epidermal growth factor) [127], TRPM2 [128], HSPG2 [129], NOX4 [130], MYH9 [131], GLIS2 [132], TRPV4 [133], GSN (gelsolin) [134], DUSP2 [135], LRP5 [136], CD248 [137], GLI1 [138], PIM1 [139], TGFB3 [140], MDK (midkine) [141], TRPC6 [142], NKD2 [143], NUAK1 [144], CYS1 [145], POSTN (periostin) [146], STAT4 [147], AEBP1 [148] and NNMT (nicotinamide N-methyltransferase) [149] might be a possible genetic markers for susceptibility to renal fibrosis. MMP12 [150], BMP2 [151], IL33 [152], SORCS1 [153], IRF4 [154], PENK (proenkephalin) [77], mellitus.…”

First person – Elia Escasany

“… ABSTRACT First Person is a series of interviews with the first authors of a selection of papers published in Disease Models & Mechanisms, helping early-career researchers promote themselves alongside their papers. Elia Escasany is first author on ‘ Transforming growth factor β3 deficiency promotes defective lipid metabolism and fibrosis in murine kidney ’, published in DMM. Elia is a PhD student in the lab of Gema Medina-Gómez at Universidad Rey Juan Carlos, Madrid, Spain, investigating the role of TGFβ in renal fibrosis.…”