Mechanisms and Modulation of Oxidative/Nitrative Stress in Type 4 Cardio-Renal Syndrome and Renal Sarcopenia

Abstract

Chronic kidney disease (CKD) is a public health problem and a recognized risk factor for cardiovascular diseases (CVD). CKD could amplify the progression of chronic heart failure leading to the development of type 4 cardio-renal syndrome (T4CRS). The severity and persistence of heart failure are strongly associated with mortality risk in T4CRS. CKD is also a catabolic state leading to renal sarcopenia which is characterized by the loss of skeletal muscle strength and physical function. Renal sarcopenia also promotes the development of CVD and increases the mortality in CKD patients. In turn, heart failure developed in T4CRS could result in chronic muscle hypoperfusion and metabolic disturbances leading to or aggravating the renal sarcopenia. The interplay of multiple factors (e.g., comorbidities, over-activated renin-angiotensin-aldosterone system [RAAS], sympathetic nervous system [SNS], oxidative/nitrative stress, inflammation, etc.) may result in the progression of T4CRS and renal sarcopenia. Among these factors, oxidative/nitrative stress plays a crucial role in the complex pathomechanism and interrelationship between T4CRS and renal sarcopenia. In the heart and skeletal muscle, mitochondria, nicotinamide adenine dinucleotide phosphate (NADPH) oxidases, uncoupled nitric oxide synthase (NOS) and xanthine oxidase are major ROS sources producing superoxide anion (O2·−) and/or hydrogen peroxide (H2O2). O2·− reacts with nitric oxide (NO) forming peroxynitrite (ONOO−) which is a highly reactive nitrogen species (RNS). High levels of ROS/RNS cause lipid peroxidation, DNA damage, interacts with both DNA repair enzymes and transcription factors, leads to the oxidation/nitration of key proteins involved in contractility, calcium handling, metabolism, antioxidant defense mechanisms, etc. It also activates the inflammatory response, stress signals inducing cardiac hypertrophy, fibrosis, or cell death via different mechanisms (e.g., apoptosis, necrosis) and dysregulates autophagy. Therefore, the thorough understanding of the mechanisms which lead to perturbations in oxidative/nitrative metabolism and its relationship with pro-inflammatory, hypertrophic, fibrotic, cell death and other pathways would help to develop strategies to counteract systemic and tissue oxidative/nitrative stress in T4CRS and renal sarcopenia. In this review, we also focus on the effects of some well-known and novel pharmaceuticals, nutraceuticals, and physical exercise on cardiac and skeletal muscle oxidative/nitrative stress in T4CRS and renal sarcopenia.

Arterial Stiffness in the Heart Disease of CKD

“…12 Moreover, nitric oxide (NO) deficiency may itself cause oxidative stress. 13 Oxidative stress can lead to endothelial dysfunction through the reduction of the endothelial production of NO, and to structural arterial stiffening through the phenotypic switching of vascular smooth muscle cells (VSMCs), the production of matrix metalloproteinases, and the inhibition of the tissue inhibitors of matrix metalloproteinases. 14 In addition, TNF activates LDL receptor gene transcription, increases alkaline phosphatase protein expression, and reduces a-smooth muscle actin protein expression.…”

Cardiac Remodeling in Chronic Kidney Disease

“…Various oxidation products have been shown to be overabundant in CKD. Increased ROS production has been reported to contribute to myocardial hypertrophy and fibrosis by lipid peroxidation, proinflammatory cytokines and DNA damage [35,36]. A marker of oxidative stress, 8-isoprostane, increases as CKD progresses [37].…”

Lipotoxicity in Kidney, Heart, and Skeletal Muscle Dysfunction

“…Yuan et al found that accumulation of truncal fat mass was associated with elevated levels of circulating hepatic growth factor (HGF), a marker for obesity in the general population, and in the presence of protein-energy wasting predicted higher mortality [127]. Other underlying mechanisms remain unknown, although some phenomena are partially explained by altered mineral metabolism, sustained inflammation, elevated oxidative/nitrative stress [128], malnutrition, and accumulated uremic toxins [122,123,124,129,130]. Recently, Jheng et al focused on ER stress in this context and clarified that uremic toxin not only promotes expression of E3 ubiquitin ligases, but also stimulates eIF2α phosphorylation and XBP1 mRNA splicing in the UPR [125].…”