Abstract
Diabetes-induced endothelial pathologies are hypothesized to lead to the progression of diabetic kidney disease (DKD). The endothelial to mesenchymal transition (EndMT) possibly induces fibrosis, leading to glomerulosclerosis in the kidney. Furthermore, this could lead to albuminuria in diabetic nephropathy due to glomerular endothelial dysfunction. Eicosapentaenoic acid (EPA), purified from fish oil, decreases inflammatory cytokine levels in glomerulonephritis. Here, we aimed at finding whether ethyl eicosapentaenoate (EPA-E) exerts renal protective effects via EndMT inhibition. To find out whether EPA inhibits EndMT in vitro, the changes in CD31 expression were studied in cultured mouse endothelial cells. The addition of the conditioned medium from the adipocyte culture significantly decreased the protein levels of CD31, while the addition of EPA-E partially reversed this inhibition. Further, EndMT inhibition by EPA-E treatment might occur via the inhibition of the protein kinase Cβ (PKCβ)/transforming growth factor-β (TGF-β)/plasminogen activator inhibitor-1 (PAI-1) signaling and not via microRNAs. Streptozotocin-induced diabetic mice fed a high-fat diet (60% from fat) exhibited mesangial expansion and albuminuria. Induction of EPA-E ameliorated the mesangial expansion and decreased albuminuria without affecting blood pressure, triglyceride and free fatty acid levels, and intraperitoneal glucose. These findings suggest that EPA-E exerts renal protective effects on endothelial cells, by normalizing EndMT followed by the PKCβ/TGF-β/PAI-1 signaling. Thus, EPA-E has the potential for imparting renal protection by regulating EndMT in DKD.
Highlights
The international diabetes foundation (IDF) reported that 463 million adults were diagnosed with diabetes in 2019, and approximately 700 million adults are expected to be diabetic by 2045 [1]
We have reported that the transforming Journal of Diabetes Research growth factor-β (TGF-β)/Smad1 pathway transcriptionally regulates the expression of Col4 and α-smooth muscle actin [11,12,13,14]
There was an increase in blood glucose by 3:2 ± 1:0-fold, kidney weight by 1:1 ± 0:4-fold, and albuminuria by 3:3 ± 0:8-fold in the diabetic mice fed a high-fat diet compared to the control mice after 5 months of diabetes
Summary
The international diabetes foundation (IDF) reported that 463 million adults were diagnosed with diabetes in 2019, and approximately 700 million adults are expected to be diabetic by 2045 [1]. The prevalence of dialysis due to DKD-induced end-stage renal disease (ESRD) has exceeded that of glomerulonephritis-related ESRD in the U.S, and the number is increasing [3]. Several large clinical studies such as the action in diabetes and vascular disease: Preterax and Diamicron modified release controlled evaluation (ADVANCE) study, the UK prospective diabetes study (UKPDS), and the action to control cardiovascular risk in diabetes (ACCORD) trial indicated that intensive glycemic control could reduce the risk of DKD [4,5,6,7]. Large randomized controlled studies including the ADVANCE study, ACCORD trial, and outcome reduction with initial glargine intervention (ORIGIN trial) showed severe hypoglycemia, serious adverse events, renal impairment, and increased mortality [5, 7, 8]. There is an urgent need to establish the new approach to treat DKD without hypoglycemia risk
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