Translational Medicine in Pulmonary-Renal Crosstalk: Therapeutic Targeting of p-Cresyl Sulfate Triggered Nonspecific ROS and Chemoattractants in Dyspneic Patients with Uremic Lung Injury

Abstract

Molecular mechanisms and pathological features of p-Cresyl sulfate (PCS)-induced uremic lung injury (ULI) in chronic kidney disease (CKD) remain unclear. We analyzed pleural effusions (PE) from CKD and non-CKD patients for uremic toxins, reactive oxygen species (ROS), and chemotactic cytokines. Correlations between PE biomarkers and serum creatinine were also studied. Cell viability and inflammatory signaling pathways were investigated in PCS-treated human alveolar cell model. To mimic human diseases, CKD-ULI mouse model was developed with quantitative comparison of immunostaining and morphometric approach. PE from CKD patients enhance expressions of uremic toxins, hydroxyl radicals, and IL-5/IL-6/IL-8/IL-10/IL-13/ENA-78/GRO α/MDC/thrombopoietin/VEGF. PE concentrations of ENA-78/VEGF/IL-8/MDC/PCS/indoxyl sulphate correlate with serum creatinine concentrations. In vitro, PCS promotes alveolar cell death, cPLA2/COX-2/aquaporin-4 expression, and NADPH oxidase/mitochondria activation-related ROS. Intracellular ROS is abrogated by non-specific ROS scavenger N-acetyl cysteine (NAC), inhibitors of NADPH oxidase and mitochondria-targeted superoxide scavenger. However, only NAC protects against PCS-induced cell death. In vivo, expressions of cPLA2/COX2/8-OHdG, resident alveolar macrophages, recruited leukocytes, alveolar space, interstitial edema and capillary leakage increase in lung tissues of CKD-ULI mice, and NAC pretreatment ameliorates alveolar–capillary injury. PCS causes alveolar–capillary injury through triggering intracellular ROS, downstream prostaglandin pathways, cell death, and activating leukocytes to release multiplex chemoattractants and extracellular ROS. Thus PCS and nonspecific ROS serve as potential therapeutic targets.

Regulation of Vascular Function and Inflammation via Cross Talk of Reactive Oxygen and Nitrogen Species from Mitochondria or NADPH Oxidase—Implications for Diabetes Progression

“…The involvement of mitochondrial ROS formation in this process was proven by lower NADPH activity in Gpx1 overexpressing mice and higher NADPH activity in Gpx1 knockout mice. A cross talk between mitochondria and NOX1 or NOX2 was also shown for cellular starvation [152], nitrate tolerance [140], the aging process [79,82,139,153], AGE/RAGE signaling [154], endotoxemia as a model of sepsis [155], dyspneic patients with uremic lung injury [156], AsO 3 toxicity [157], idiopathic pulmonary fibrosis [158], and tumorigenesis [159]. Even a triple cross talk between NOX4, NOX2, and mitochondria as well as ROS-induced ROS release was described in vascular endothelial growth factor (VEGF) signaling and angiogenesis [160].…”

Scavenging Intracellular ROS Attenuates p-Cresyl Sulfate-Triggered Osteogenesis through MAPK Signaling Pathway and NF-κB Activation in Human Arterial Smooth Muscle Cells

“…We previously reported that intracellular sources of ROS induced by PCS are multifaceted, including NADPH oxidase and mitochondria [8]. Our prior findings elucidated single inhibitors for NADPH oxidase-derived ROS and mitochondria-targeted superoxide could not abrogate downstream inflammatory responses to attenuate cell damages, reflecting the underlying signaling transduction network is intricate.…”

“…The representative protein-bound uremic toxins (PBUT), p-cresyl sulfate (PCS) and indoxyl sulfate (IS), exert pro-oxidant and pro-inflammatory effects on diverse cell and organ systems [8,9] PCS mainly presents as a protein-bound form in the blood circulation, and this study is focusing on the free form of PCS [10]. Experimental data from cell and animal models suggest that reactive oxygen species (ROS) and chronic sustained inflammation resting from circulating PTUB are hallmarks of UVC and capable of pivotal inducers of osteogenesis in human arterial smooth muscle cell (HASMC) [11].…”

A Joint Evaluation of Impaired Cardiac Sympathetic Responses and Malnutrition-Inflammation Cachexia for Mortality Risks in Hemodialysis Patients

“…Alternately, excess nitric oxide production may result in peroxynitrite production, endothelial damages, and neuron injuries, a process referred to as nitrosative stress (28,29). Meanwhile, the burden of pro-inflammatory and pro-oxidant state is reminiscent of uremic milieu in chronic kidney disease (30). In light of this, ESRD patients superimposed on DM would be at the greatest risk of impaired CSR related death.…”