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Differences in the effects of ACEIs and ARBs are not well studied and the mechanisms responsible are not well understood.<\/jats:p><\/jats:sec><jats:sec><jats:title>Experimental Approach<\/jats:title><jats:p>Male diabetic CD\u20101 mice were treated with ACEI, ARB, <jats:italic>N<\/jats:italic>\u2010acetyl\u2010seryl\u2010aspartyl\u2010lysyl\u2010proline (AcSDKP), ACEI + AcSDKP, ARB + AcSDKP, glycolysis inhibitors or non\u2010treatment. Moreover, prolyl oligopeptidase inhibitor (POPi)\u2010injected male diabetic C57Bl6 mice were treated with ACEI, AcSDKP and ARB or non\u2010treatment. Western blot and immunofluorescent staining were used to examine key enzymes and regulators of central metabolism.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key Results<\/jats:title><jats:p>The antifibrotic action of ACEI imidapril is due to an AcSDKP\u2010mediated antifibrotic mechanism, which reprograms the central metabolism including restoring SIRT3 protein and mitochondrial fatty acid oxidation and suppression of abnormal glucose metabolism in the diabetic kidney. Moreover, the POPi S17092 significantly blocked the AcSDKP synthesis, accelerated kidney fibrosis and disrupted the central metabolism. ACEI partly restored the kidney fibrosis and elevated the AcSDKP level, whereas the ARB (TA\u2010606) did not show such effects in the POPi\u2010injected mice. 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