Oxidative Stress and Renal Fibrosis: Recent Insights for the Development of Novel Therapeutic Strategies

Abstract

Chronic kidney disease (CKD) is a significant worldwide healthcare problem. Regardless of the initial injury, renal fibrosis is the common final pathway leading to end stage renal disease. Although the underlying mechanisms are not fully defined, evidence indicates that besides inflammation, oxidative stress plays a crucial role in the etiology of renal fibrosis. Oxidative stress results from an imbalance between the production of free radicals that are often increased by inflammation and mitochondrial dysfunction, and reduced anti-oxidant defenses. Several studies have demonstrated that oxidative stress may occur secondary to activation of transforming growth factor β1 (TGF-β1) activity, consistent with its role to increase nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (Nox) activity. A number of other oxidative stress-related signal pathways have also been identified, such as nuclear factor erythroid-2 related factor 2 (Nrf2), the nitric oxide (NO)-cyclic guanosine monophosphate (cGMP)-cGMP-dependent protein kinase 1-phosphodiesterase (cGMP-cGK1-PDE) signaling pathway, and the peroxisome proliferator-activated receptor gamma (PPARγ) pathway. Several antioxidant and renoprotective agents, including cysteamine bitartrate, epoxyeicosatrienoic acids (EETs), and cytoglobin (Cygb) have demonstrated ameliorative effects on renal fibrosis in preclinical or clinical studies. The mechanism of action of many traditional Chinese medicines used to treat renal disorders is based on their antioxidant properties, which could form the basis for new therapeutic approaches. This review focuses on the signaling pathways triggered by oxidative stress that lead to renal fibrosis and provides an update on the development of novel anti-oxidant therapies for CKD.

Reduction of cellular stress is essential for Fibroblast growth factor 1 treatment for diabetic nephropathy

“…DN is a serious and common complication of diabetes, which leads to end‐stage kidney disease, and therefore, it is important to illuminate the mechanisms and explore the effective therapeutic strategy for DN. Specific treatment of patients with diabetic nephropathy can be divided into 4 major arenas: cardiovascular risk reduction, glycemic control, blood pressure control, and inhibition of the renin‐angiotensin system (RAS) .…”

“…Our current study had demonstrated that FGF1 treatment blocked diabetes‐associated α‐SMA overexpression and collagen accumulation. Histologically, progressive kidney disease is marked by renal fibrosis and glomerulosclerosis . It is well known that α‐SMA is the marker of cell transdifferentiation, including epithelial–mesenchymal transition (EMT) and fibroblast activation into myofibroblast, which importantly contributes to the progression of CKD .…”

“…Cellular stress is a component of the development of various kidney diseases . Our mechanism studies have revealed that elevated oxidative stress and ER stress are the causal events for diabetes‐related complications .…”

“…Oxidative stress is a condition in which generation of reactive oxygen species (ROS) exceeds the capacity of the antioxidant defense system, caused by increased ROS production and impaired antioxidant capacity . Subsequent studies have also implicated that the NADPH oxidases (NOX) family of enzymes as major cytosolic sources of superoxide, and it is now appreciated that several sources exist within the cell that contribute to the increased oxidative stress accompanying diabetes . It has been demonstrated hyperglycemia induces oxidative and nitrosative stress, and increases renal functional impairment via nuclear factor erythroid‐2 related factor 2 (Nrf2) signalling .…”

“…Cellular stress is a component of the development of various kidney diseases. 3,4 Our mechanism studies have revealed that elevated oxidative stress and ER stress are the causal events for diabetes-related complications. 5,6 Oxidative stress is a condition in which generation of reactive oxygen species (ROS) exceeds the capacity of the antioxidant defense system, caused by increased ROS production and impaired antioxidant capacity.…”