Oxidative Stress as a Major Culprit in Kidney Disease in Diabetes

Abstract

It is postulated that localized tissue oxidative stress is a key component in the development of diabetic nephropathy. There remains controversy, however, as to whether this is an early link between hyperglycemia and renal disease or develops as a consequence of other primary pathogenic mechanisms. In the kidney, a number of pathways that generate reactive oxygen species (ROS) such as glycolysis, specific defects in the polyol pathway, uncoupling of nitric oxide synthase, xanthine oxidase, NAD(P)H oxidase, and advanced glycation have been identified as potentially major contributors to the pathogenesis of diabetic kidney disease. In addition, a unifying hypothesis has been proposed whereby mitochondrial production of ROS in response to chronic hyperglycemia may be the key initiator for each of these pathogenic pathways. This postulate emphasizes the importance of mitochondrial dysfunction in the progression and development of diabetes complications including nephropathy. A mystery remains, however, as to why antioxidants per se have demonstrated minimal renoprotection in humans despite positive preclinical research findings. It is likely that the utility of current study approaches, such as vitamin use, may not be the ideal antioxidant strategy in human diabetic nephropathy. There is now an increasing body of data to suggest that strategies involving a more targeted antioxidant approach, using agents that penetrate specific cellular compartments, may be the elusive additive therapy required to further optimize renoprotection in diabetes.

Effect of dietary inclusions of bitter kola seed on geotactic behavior and oxidative stress markers in Drosophila melanogaster

“…The oxidative stress hypothesis of aging has been well reported in various animal models (Forbes, Coughlan, & Cooper, 2008; Negre‐Salvayre, Salvayre, Auge, Pamplona, & Portero‐Otin, 2009). Specifically, there have been several reports implicating ROS generation and oxidative stress in reduced life span in D. melanogaster (Hyrsl, Büyükgüzel, & Büyükgüzel, 2007; Lozinsky, Lushchak, Storey, Storey, & Lushchak, 2012; Lozinsky et al., 2013).…”

Hydrogen Sulfide Alleviates Diabetic Nephropathy in a Streptozotocin-induced Diabetic Rat Model

“…A number of ROS-generating pathways such as glycolysis, specific defects in the polyol pathway, uncoupling of nitric oxide synthase, xanthine oxidase, NAD(P)H oxidase, and advanced glycation have been identified as potentially major contributors to the pathogenesis of diabetic nephropathy. In addition, mitochondrial production of ROS in response to chronic hyperglycemia may be the key initiator for each of these pathogenic pathways (10). Several components of the diabetic milieu, such as hyperglycemia, advanced glycation end products, and immunocomplexes, can activate kidney cells via induction of stress-activated protein kinase signaling, resulting in the release of chemokines and upregulation of cell adhesion molecules.…”

Activated protein C ameliorates diabetic nephropathy by epigenetically inhibiting the redox enzyme p66 Shc

“…The potential relevance of the antioxidant properties of aPC is further supported by its potent nephroprotective effects in a mouse model of diabetic nephropathy (6,7). Mitochondrial dysfunction resulting in the generation of ROS is considered to be a unifying mechanism underlying diabetic vascular complications, including diabetic nephropathy (8,9). aPC efficiently suppresses the glucose-induced release of cytochrome c and Smac/Diablo from mitochondria and mitochondrial apoptosis in vitro and reduces peroxynitrite formation (ONOO − , resulting from a reaction of NO − with O 2 − ) in diabetic kidneys in vivo (7).…”