From kidney injury to cardiac dysfunction: the central role of oxidative stress in diabetes and CKD.

Both diabetes mellitus (DM) and chronic kidney disease (CKD) predispose to cardiac remodeling and coronary microvascular dysfunction, which is proposed to be mediated through increased oxidative stress. To link oxidative stress and cardiac remodeling in DM and CKD, CKD was induced in genetically modified DM swine (INS(C94Y) transgenic) at 10-12 weeks of age via renal microembolization, while non-embolized DM and wild-type (WT) swine served as controls. Compared to WT, 1) DM animals displayed modest LV dilation and a slight decline in ejection fraction, with increased end-systolic pressures and coronary blood flow. Addition of CKD did not further aggravate these alterations, but increased the pressure and diastolic wall stress compared to WT. 2) Proteomic analysis revealed enrichment in metabolic pathways involving fatty acids and glutamate, thus highlighting substantial metabolic reprogramming in both DM and DM_CKD groups. Re-analysis of proteomic data from human HFpEF patients showed differential regulation of similar pathways as well as anti-oxidant enzymes. 3) Isolated mitochondrial respiration was reduced in DM and DM_CKD hearts across multiple substrates (fatty acids, pyruvate-malate, glutamate-malate, and succinate), implicating broad mitochondrial dysfunction. 4) DM_CKD animals showed heightened oxidative stress in both coronary vasculature and myocardium as compared to both WT and DM [13 ± 3 (WT), 14 ± 3 (DM) and 39 ± 10% positive nuclei (DM_CKD)]. 5) LV-interstitial fibrosis was increased in DM_CKD (3.72 ± 0.50%) vs WT (1.70 ± 0.29%), with DM having an intermediate phenotype (2.82 ± 0.37%). Thus, even mild CKD in the presence of DM is accompanied by oxidative stress and ECM deposition. Our findings highlight the critical role of CKD in accelerating cardiac pathology and underscore the importance of targeting the cardiorenal axis in future therapeutic strategies.