<p>Renal denervation (RDN) reduces cardiac sympathetic nerve activity maintained by arterial hypertension. This study aimed to investigate whether RDN affects myocardial mitochondrial oxidative stress and myocardial fibrosis through norepinephrine (NE)/Kruppel-like factor 15 (KLF15)/renalase (RNLS) pathway. The impact of RDN on myocardial remodeling was assessed in rats subjected to transverse aortic coarctation (TAC) surgery. To explore the mechanism by which NE influences mitochondrial oxidative stress and fibrosis in AC16 cardiomyocytes, we intervened with KLF15 and RNLS. The molecular mechanism underlying the role of RDN in TAC-induced myocardial remodeling was achieved through intraperitoneal injection of NE and adeno-associated virus to knock down KLF15 and RNLS. Echocardiography showed that RDN increased left ventricular ejection fraction and fractional shortening in TAC rats, while decreasing left ventricular end-systolic diameter. RDN decreased the myocardial infarction size, myocardial tissue injury, and fibrosis; decreased serum NE level; increased RNLS level; and promoted KLF15 and RNLS expression in cardiac tissue in TAC rats. NE prevented RDN effects on TAC rats. Further results showed that RDN improved myocardial remodeling in TAC rats by upregulating RNLS. NE promoted mitochondrial oxidative stress and fibrosis in cardiomyocytes by inhibiting RNLS. Mechanically, NE aggravated mitochondrial oxidative stress and fibrosis of cardiomyocytes by inhibiting KLF15 to downregulate RNLS. Moreover, RDN improved myocardial remodeling in TAC rats by upregulating KLF15. Our results implicated that RDN improved mitochondrial oxidative stress and myocardial fibrosis by inhibiting the NE/KLF15/RNLS pathway. Our findings demonstrated that the NE/KLF15/RNLS axis is a molecular strategy for RDN treatment of myocardial fibrosis.</p>