Pathogenesis of Chronic Cardiorenal Syndrome: Is There a Role for Oxidative Stress?

Abstract

Cardiorenal syndrome is a frequently encountered clinical condition when the dysfunction of either the heart or kidneys amplifies the failure progression of the other organ. Complex biochemical, hormonal and hemodynamic mechanisms underlie the development of cardiorenal syndrome. Both in vitro and experimental studies have identified several dysregulated pathways in heart failure and in chronic kidney disease that lead to increased oxidative stress. A decrease in mitochondrial oxidative metabolism has been reported in cardiomyocytes during heart failure. This is balanced by a compensatory increase in glucose uptake and glycolysis with consequent decrease in myocardial ATP content. In the kidneys, both NADPH oxidase and mitochondrial metabolism are important sources of TGF-β1-induced cellular ROS. NOX-dependent oxidative activation of transcription factors such as NF-kB and c-jun leads to increased expression of renal target genes (phospholipaseA2, MCP-1 and CSF-1, COX-2), thus contributing to renal interstitial fibrosis and inflammation. In the present article, we postulate that, besides contributing to both cardiac and renal dysfunction, increased oxidative stress may also play a crucial role in cardiorenal syndrome development and progression. In particular, an imbalance between the renin-angiotensin-aldosterone system, the sympathetic nervous system, and inflammation may favour cardiorenal syndrome through an excessive oxidative stress production. This article also discusses novel therapeutic strategies for their potential use in the treatment of patients affected by cardiorenal syndrome.

Free Radicals and Biomarkers Related to the Diagnosis of Cardiorenal Syndrome

“…In response, the most prominent adaptive processes accompanying HF are an increase in sympathetic tone. Increased adrenergic activity causes a reduction on the physiological role of respirasomes, and consequently mitochondrial dysfunction, and a gradual decrease in the cardiac performance [28]. The excessive sympathetic activity can induce cardiomyocyte apoptosis, hypertrophy, and focal myocardial necrosis [85].…”

“…In addition, ROS has been implicated in the induction and in the complications of cardiac and renal [27] dysfunctions related to CRS [28] through the SNS and the RAAS [29].…”

“…Taking into account the kidney and the heart to explain the role of the free radicals, Rubattu et al [28] published a review about pathogenesis of CRS and oxidative stress. The information is addressed briefly in the next paragraphs.…”

“…According to Yang and Liu [183], and to Rubattu et al [28], EMT regulates the loss of epithelial cell adhesion, the de novo α-smooth muscle actin (α-SMA) expression and reorganization, the disruption of tubular basement membrane, and the enhanced cell migration and invasion into the interstitium. Increased expressions of PLA2, MCP-1, CSF-1, and COX-2 promote fibrosis and inflammation on renal interstitium, all due to NOX activation under oxidative stress progression [184][185][186][187].…”

A review of the impact of oxidative stress and some antioxidant therapies on renal damage

“…Various studies have reported that in patients with renal failure, an altered redox balance results from greater levels of ROS, RNS and some toxins together with an impaired antioxidant capacity. [10][11][12][13][14] An increase in reactive species is known to be involved in inflammatory glomerular injury by stimulating the overproduction of several mediators, including cytokines and chemokines. One of the most important of these mediators is nuclear factor kappa beta (NF-kb).…”