Metabolic reprogramming by N-acetyl-seryl-aspartyl-lysyl-proline protects against diabetic kidney disease.

BACKGROUND AND
PURPOSE: ACE inhibitors (ACEIs) and AT1 receptor antagonists (ARBs) are first-line drugs that are believed to reduce the progression of end-stage renal disease in diabetic patients. Differences in the effects of ACEIs and ARBs are not well studied and the mechanisms responsible are not well understood. EXPERIMENTAL APPROACH: Male diabetic CD-1 mice were treated with ACEI, ARB, N-acetyl-seryl-aspartyl-lysyl-proline (AcSDKP), ACEI + AcSDKP, ARB + AcSDKP, glycolysis inhibitors or non-treatment. Moreover, prolyl oligopeptidase inhibitor (POPi)-injected male diabetic C57Bl6 mice were treated with ACEI, AcSDKP and ARB or non-treatment. Western blot and immunofluorescent staining were used to examine key enzymes and regulators of central metabolism. KEY
RESULTS: The antifibrotic action of ACEI imidapril is due to an AcSDKP-mediated 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-606) did not show such effects in the POPi-injected mice. ACE inhibition and AcSDKP suppressed defective metabolism-linked mesenchymal transformations and reduced collagen-I and fibronectin accumulation in the diabetic kidneys. CONCLUSION AND IMPLICATIONS: The study envisages that AcSDKP is the endogenous antifibrotic mediator that controls the metabolic switch between glucose and fatty acid metabolism and that suppression of AcSDKP leads to disruption of kidney cell metabolism and activates mesenchymal transformations leading to severe fibrosis in the diabetic kidney.