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We aimed to test whether chronic systemic inhibition of miR-451 would enhance renal fibrosis (associated with deranged autophagy). Adult TallyHo\/Jng mice (obese insulin resistant) were randomized to two treatment groups to receive either miR-451 inhibition [via a locked nucleic acid construct] or a similar scrambled locked nucleic acid control for 8 wk. All mice were fed a high-fat diet (60% kcal from fat) ad libitum and humanely euthanized after 12 wk. Kidneys and blood were collected for analysis. Renal expression of miR-451 was sixfold lower in inhibitor-treated mice compared with control mice. miR-451 inhibition increased kidney weight and collagen and glycogen deposition. Blood chemistry revealed significantly higher Na<jats:sup>+<\/jats:sup> and anion gap (relative metabolic acidosis) in inhibitor-treated mice. Western blot analysis and immunohistochemistry of the kidney revealed that the inhibitor increased markers of renal injury and fibrosis, e.g., kidney injury molecule 1, neutrophil gelatinase-associated lipocalin, transforming growth factor-\u03b2, 14-3-3 protein-\u03b6, mechanistic target of rapamycin, AMP-activated protein kinase-\u03b1, calcium-binding protein 39, matrix metallopeptidase-9, and the autophagy receptor sequestosome 1. In contrast, the inhibitor reduced the epithelial cell integrity marker collagen type IV and the autophagy markers microtubule-associated protein 1A\/1B light chain 3B and beclin-1. 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