Krill Oil Turns Off TGF-β1 Profibrotic Signaling in the Prevention of Diabetic Nephropathy

Abstract

Diabetic nephropathy (DN), a severe microvascular complication of diabetes mellitus (DM), results in high mortality due to the lack of effective interventions. The current study investigated the preventive effect of krill oil (KO) on DN using a type 2 DM mouse model induced by streptozotocin and high-fat diet for 24 weeks. The diabetic mice developed albuminuria, mesangial matrix accumulation, glomerular hypertrophy, and fibrosis formation, with an increase in renal proinflammatory, oxidative and profibrotic gene expression. KO significantly prevented these effects but did not improve hyperglycemia and glucose intolerance. In high-glucose-treated mesangial cells (MCs), KO preferably modulated TGF-β1 signaling as revealed by RNA-sequencing. In TGF-β1-treated MCs, KO abolished SMAD2/3 phosphorylation and nuclear translocation and activated Smad7 gene expression. The action of KO on the SMADs was confirmed in the diabetic kidneys. Therefore, KO may prevent DN predominantly by suppressing the TGF-β1 signaling pathway.

Local Application of Krill Oil Accelerates the Healing of Artificially Created Wounds in Diabetic Mice

“…KO has been reported to have anti-inflammatory, anti-oxidative, and anti-fibrotic activities in mouse models of diabetic complications [ 11 , 12 , 27 ]. We previously found that KO could inhibit DM-induced cardiac and renal inflammation and fibrosis, preventing diabetic cardiomyopathy and nephropathy in a mouse model of T2DM [ 11 , 12 ]. In line with these findings, in the present study, KO was found to attenuate cutaneous inflammation in the diabetic wounds ( Figure 3 ).…”

“…However, different from the anti-fibrotic effect of KO on the diabetic hearts and kidneys, KO generated cutaneous fibrosis in the diabetic mice ( Figure 5 ). In particular, KO activated the cutaneous expression of TGF-β1, α-SMA, and collagen as the initiator, intermediate product, and end product of fibrosis ( Figure 5 ), respectively, whereas TGF-β1 signaling and the expression of α-SMA and collagen were significantly inhibited by KO in the diabetic hearts and kidneys [ 11 , 12 ]. The discrepancy between the effects of KO on fibrosis in different tissues might be attributed to the different cell identities during the pathogenesis of diabetic complications.…”

“…The blood glucose levels and body weight were monitored every 4 weeks. At the end of the sixth week post DM, a glucose tolerance test (GTT) was performed as previously described [ 11 ]. The composition of the experimental diets is listed in Table S1 .…”

“…IHC staining was carried out as previously described [ 11 ], using primary antibodies against CD31 (1:200, Proteintech, Wuhan, Hubei, China) and F4/80 (1:400, Cell Signaling Technology, Shanghai, China).…”

“…Rich in docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA), and astaxanthin (AST), KO has strong anti-inflammatory and anti-oxidative activities [ 10 ]. We previously found that KO could inhibit DM-induced inflammation and oxidative stress, ameliorating diabetic nephropathy and cardiomyopathy [ 11 , 12 ]. KO has also been reported by other groups to protect against diabetic neuropathy and intestinal inflammation [ 13 , 14 ].…”