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Renal denervation ameliorates cardiac metabolic remodeling in diabetic cardiomyopathy rats by suppressing renal SGLT2 expression

Abstract

This study aimed to investigate the effects of renal denervation (RDN) on diabetic cardiomyopathy (DCM) and explore the related mechanisms. Male Sprague-Dawley rats were fed high-fat chow and injected with low-dose streptozotocin to establish a DCM model. Six rats served as controls. The surviving rats were divided into three groups: control group, DCM group and DCM + RDN group. RDN surgery was performed in the fifth week. At the end of the experiment, all rats were subjected to 18F-FDG PET/CT and metabolic cage studies. Cardiac function and structure were evaluated by echocardiography and histology. Myocardial substrate metabolism and mitochondrial function were assessed by multiple methods. In the 13th week, the DCM rats exhibited cardiac hypertrophy and interstitial fibrosis accompanied by diastolic dysfunction. RDN ameliorated DCM-induced cardiac dysfunction (E/A ratio: RDN 1.07 ± 0.18 vs. DCM 0.93 ± 0.12, P < 0.05; E/E’ ratio: RDN 10.74 ± 2.48 vs. DCM 13.25 ± 1.99, P < 0.05) and pathological remodeling (collagen volume fraction: RDN 5.05 ± 2.05% vs. DCM 10.62 ± 2.68%, P < 0.05). Abnormal myocardial metabolism in DCM rats was characterized by suppressed glucose metabolism and elevated lipid metabolism. RDN increased myocardial glucose uptake and oxidation while reducing the absorption and utilization of fatty acids. Meanwhile, DCM decreased mitochondrial ATP content, depolarized the membrane potential and inhibited the activity of respiratory chain complexes, but RDN attenuated this mitochondrial damage (ATP: RDN 30.98 ± 7.33 μmol/gprot vs. DCM 22.89 ± 5.90 μmol/gprot, P < 0.05; complexes I, III and IV activity: RDN vs. DCM, P < 0.05). Furthermore, both SGLT2 inhibitor and the combination treatment produced similar effects as RDN alone. Thus, RDN prevented DCM-induced cardiac dysfunction and pathological remodeling, which is related to the improvement of metabolic disorders and mitochondrial dysfunction.

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Fig. 1: RDN effectively promoted urinary glucose excretion in DCM rats.
Fig. 2: RDN ameliorated DCM-induced cardiac dysfunction and pathological remodeling.
Fig. 3: RDN improved myocardial glucose metabolism abnormalities.
Fig. 4: RDN regulated myocardial lipid metabolism and promoted the utilization of ketone bodies.
Fig. 5: RDN ameliorated mitochondrial dysfunction in DCM rats.
Fig. 6: The protective effects of RDN were mediated by regulation of renal SGLT2 expression.
Fig. 7: Comparison between RDN and SGLT2i on the effect of DCM.

Data availability

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Funding

This study was supported by the National Natural Science Foundation of China (No. 81770333, No. 81800350).

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Contributions

J.Y.H. and W.Y.J. performed nearly all the experiments and were the major contributors to the writing of the manuscript. S.G.Z. and Y.T.L. performed the 18F-FDG PET/CT and metabolic cage studies. J.G. and M.C. performed the echocardiographic and electron microscopic studies. J.G. and Y.Y.C. conducted and analyzed the mitochondrial function measurements. Q.J.S. and Z.X.J. were the corresponding authors, and all the experiments were performed under their guidance. All authors read and approved the final paper.

Corresponding authors

Correspondence to Zhi-Xin Jiang or Qi-Jun Shan.

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The authors declare no competing interests.

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All animal experiments in this study were approved by the Ethics Committee of Nanjing Medical University (IACUC-2011003).

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Huo, JY., Jiang, WY., Zhang, SG. et al. Renal denervation ameliorates cardiac metabolic remodeling in diabetic cardiomyopathy rats by suppressing renal SGLT2 expression. Lab Invest 102, 341–351 (2022). https://doi.org/10.1038/s41374-021-00696-1

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