Abstract
Epidemiologic studies showed the correlation between the deficiency of omega-3 polyunsaturated fatty acids (n-3 PUFAs) and the progression of chronic kidney diseases (CKD), however, the role and mechanisms for n-3 PUFAs in protecting against kidney fibrosis remain obscure. In this study, NRK-49F cells, a rat kidney interstitial fibroblast cell line, were stimulated with TGFβ1. A Caenorhabditis elegans fat-1 transgenic mouse model in which n-3 PUFAs are endogenously produced from n-6 PUFAs owing to the expression of n-3 fatty acid desaturase were deployed. Docosahexaenoic acid (DHA), one member of n-3 PUFAs family, could suppress TGFβ1-induced fibroblast activation at a dose and time dependent manner. Additionally, DHA could largely inhibit TGFβ1-stimulated Akt but not S6 or Smad3 phosphorylation at a time dependent manner. To decipher the role for n-3 PUFAs in protecting against kidney fibrosis, fat-1 transgenic mice were operated with unilateral ureter obstruction (UUO). Compared to the wild types, fat-1 transgenics developed much less kidney fibrosis and inflammatory cell accumulation accompanied by less p-Akt (Ser473), p-Akt (Thr308), p-S6 and p-Smad3 in kidney tissues at day 7 after UUO. Thus, n-3 PUFAs can attenuate fibroblast activation and kidney fibrosis, which may be associated with the inhibition of mTORC2 signaling.
Highlights
Polyunsaturated acids (PUFAs) are the principal composition of lipid which forms cellular membrane as well as second signaling messengers in mammal cells[2]
We found that Docosahexaenoic acid (DHA), one member of n-3 PUFAs, could largely abolish TGFβ1 -induced fibroblast activation accompanied by a reduction of Akt but not S6 or Smad[3] phosphorylation in NRK-49F cells
This study suggests that n-3 PUFAs protect against kidney fibroblast activation and kidney fibrosis, which may be associated with the inhibition of mTORC2 signaling pathway
Summary
Polyunsaturated acids (PUFAs) are the principal composition of lipid which forms cellular membrane as well as second signaling messengers in mammal cells[2]. It was reported that human beings selected and evolved on an ideal diet with the n-3/n-6 PUFAs ratio of 1:1 before the agricultural revolution[6]. This ratio has been changed to 1:20 over the past 150 years due to the less n-3 and excess n-6 PUFAs in our modern diets[7,8]. Large variation for the amount and sources of n-3 PUFAs as well as the rapid oxidation of PUFAs in diets may account for the discrepancy of PUFAs in treating patients or animals with CKD. This study suggests that n-3 PUFAs protect against kidney fibroblast activation and kidney fibrosis, which may be associated with the inhibition of mTORC2 signaling pathway
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