Ameliorative effect of docosahexaenoic acid-acylated astaxanthin ester on diabetic nephropathy: association with the trehalose/HSP90AA1 and colon–kidney axis

Abstract

As a severe microvascular complication of diabetes, diabetic nephropathy (DN) lacks safe and effective preventive interventional strategies. Previous enterostomy-based colonic perfusion studies have shown that colon-targeted DHA delivery has superior hypoglycemic efficacy to intragastric or intrajejunal administration, though its invasiveness limits clinical translation. Notably, the naturally occurring esterified form of DHA and astaxanthin (DHA-acylated astaxanthin ester, DHA-AST) has been reported to exhibit intrinsic colon-targeted delivery properties. Here we report that oral DHA-AST exerts a significant renoprotective effect against DN in a preventive intervention model of KKAy mice, with superior efficacy to an equimolar DHA in combination with AST (DHA+AST). Specifically, relative to the DHA+AST group, DHA-AST gavage achieved selective colonic DHA enrichment, more effectively ameliorated systemic glucose dyshomeostasis, renal dysfunction, and histopathological damage, and suppressed renal inflammation, oxidative stress and fibrosis. These renoprotective effects were observed alongside improvements in systemic glucose homeostasis. Integrated multi-omics analyses revealed that DHA-AST remodeled gut microbiota composition and associated metabolic profiles, increased colonic trehalose production, and promoted the accumulation of trehalose in the kidneys. Oral trehalose supplementation partially phenocopied the renoprotective effects of DHA-AST against DN in KKAy mice. Combined network pharmacology and molecular docking assays identified HSP90AA1 as a putative molecular target of trehalose. Functional validation using TGF-β1-challenged glomerular mesangial cells showed that recombinant HSP90AA1 protein reversed the inhibitory effect of trehalose on profibrotic gene expression, whereas HSP90AA1 knockdown enhanced this effect. These findings demonstrate that DHA-AST ameliorates DN in association with a putative colon-kidney axis involving trehalose and HSP90AA1, providing preclinical evidence for the development of DHA-AST and trehalose as nutritional intervention candidates for DN.