Extracellular Superoxide Dismutase Protects against Proteinuric Kidney Disease

Abstract

Extracellular superoxide dismutase (EC-SOD), also known as SOD3, is an antioxidant expressed at high levels in normal adult kidneys. Because oxidative stress contributes to a variety of kidney injuries, we hypothesized that EC-SOD may be protective in CKD progression. To study this hypothesis, we used a murine model of ADR nephropathy characterized by albuminuria and renal dysfunction. We found that levels of EC-SOD diminished throughout the course of disease progression and were associated with increased levels of NADPH oxidase and oxidative stress markers. EC-SOD null mice were sensitized to ADR injury, as evidenced by increases in albuminuria, serum creatinine, histologic damage, and oxidative stress. The absence of EC-SOD led to increased levels of NADPH oxidase and an increase in b-catenin signaling, which has been shown to be pathologic in a variety of kidney injuries. Exposure of EC-SOD null mice to either chronic angiotensin II infusion or to daily albumin injections also caused increased proteinuria. In contrast, EC-SOD null mice subjected to nonproteinuric CKD induced by unilateral ureteral obstruction exhibited no differences compared with wild-type mice. Finally, we also found a decrease in EC-SOD in human CKD biopsy samples, similar to our findings in mice. Therefore, we conclude that EC-SOD is protective in CKDs characterized by proteinuria.

Effects of Single and Combined Losartan and Tempol Treatments on Oxidative Stress, Kidney Structure and Function in Spontaneously Hypertensive Rats with Early Course of Proteinuric Nephropathy

“…The alterations in renal function in SHR with ADR nephropathy, as noticed by the development of massive proteinuria in this study, were also accompanied by a significant reduction of SOD and GSH-Px activities in the kidney. The above findings are consistent with those previously reported in diabetic and ADR-induced nephropathy [11,28–30]. Because ADR accumulates mainly in the kidney [31], and given that the kTBARS remained unchanged after ADR treatment in the present study, similar to results obtained by Zima et al in Wistar rats [32] or in BALC/c mice with early ADR nephropathy one week after application of 10mg/kg [28], we performed protein carbonyl test to find out whether protein carbonilation, an irreversible process induced in vivo by all types of reactive oxygen and nitrogen species including peroxynitrite, and followed by loss of enzymatic activities, loss of ligand binding properties, increased susceptibility to proteolytic activities, aggregation, and modification in the transcriptional activities [7], could participate in ADR-induced nephropathy in SHR.…”

“…Increased PCOs in the kidney of SHADR group was associated with a significant reduction in the antioxidant enzyme activities of kSOD and kGSH-Px. These results were consistent with the findings described by others in diabetic rats [11], and ADR-induced nephropathy models [22,28–30]. Taking into account that peroxynitrite when acts as an oxidant produces nitrite and hydroxide ion rather than isomerizing to nitrate [33], we hypothesized that the increased nitrite production in the kidney of SHADR and the reduced level of nitrate that we observed compared to SHC, indicated an elevated level of peroxynitrite induced protein oxidation in this group, thus in conditions of reduced kidney antioxidant defense contributed to the deterioration of renal structure and function in this model of proteinuric nephropathy.…”

Keap1 hypomorphism protects against ischemic and obstructive kidney disease

“…It is also not surprising that enhancement of antioxidants such as NQO1, catalase, and the SODs are protective in renal disease. We recently described a protective role for SOD3 during kidney injury as well as a loss of this antioxidant from the kidney during disease states40. We further discovered that NQO1 was largely localized to a subset of renal tubules prior to injury.…”

Extracellular superoxide dismutase, a molecular transducer of health benefits of exercise

“…Acute kidney injury (AKI). Mouse models in which the EcSOD gene is mutated or SOD inhibitors are used suggest protective role of EcSOD against renal injury (19,45,95,104).…”

“…EcSOD -/mice were more susceptible to histological damage, oxidative stress and increased serum creatinine caused by adverse drug reaction (104). Similarly, when SOD inhibitor was used in a rat sepsis model induced by cecal ligation-puncture (CLP), renal blood flow decreased and nitrotyrosine content increased 48 hours post CLP (19).…”