Renoprotective effect of long acting thioredoxin by modulating oxidative stress and macrophage migration inhibitory factor against rhabdomyolysis-associated acute kidney injury

Abstract

Rhabdomyolysis-associated acute kidney injury (AKI) is a serious life-threatening condition. As such, more effective strategies are needed for its prevention. Thioredoxin-1 (Trx), a redox-active and macrophage migration inhibitory factor (MIF) modulating protein, has a short retention time in the blood. We examined the renoprotective effect of long acting Trx that was genetically fused with human serum albumin (HSA-Trx) against glycerol-induced AKI. An intravenous HSA-Trx pre-treatment attenuated the glycerol-induced decline in renal function, compared to a PBS, HSA or Trx alone. HSA-Trx caused a reduction in the tubular injuries and in the number of apoptosis-positive tubular cells. Renal superoxide, 8-hydroxy deoxyguanosine, nitrotyrosine and the plasma Cys34-cysteinylated albumin were clearly suppressed by the HSA-Trx treatment. Prior to decreasing TNF-α and IL-6, HSA-Trx suppressed an increase of plasma MIF level. In LLC-PK1 cells, HSA-Trx decreased the level of reactive oxygen species and lactate dehydrogenase release induced by myoglobin. HSA-Trx treatment resulted in a threefold increase in the survival of lethal glycerol-treated mice. The post-administration of HSA-Trx at 1 and 3 hr after glycerol injection exerted a significant renoprotective effect. These results suggest HSA-Trx has potential for use in the treatment of rhabdomyolysis-associated AKI via its extended effects of modulating oxidative stress and MIF.

Non-Transgenic Mouse Models of Kidney Disease

“…Hence, in this animal model, measurement of the GFR or creatinine clearance should be preferred. Nishida et al [30] reported a significant reduction of endogenous creatinine clearance 24 h after glycerol injection.…”

“…In SCID mice, intramuscular injection of 7.5 ml/kg glycerol results in maximum elevation of BUN and serum creatinine after 24 h and remains elevated for 5 days to normalize thereafter [32]. Histopathological analysis shows tubular damage, which is most severe in the renal corticomedullary boundary zone [30]. …”

“…It is assumed that myoglobin damages tubular cells via oxidative stress and inflammation and leads to renal vasoconstriction [30,31]. To induce acute kidney failure an appropriate dose of glycerol (5-10 ml/kg 50% glycerol) has to be injected intramuscularly into the hind limbs of mice.…”

“…To induce acute kidney failure an appropriate dose of glycerol (5-10 ml/kg 50% glycerol) has to be injected intramuscularly into the hind limbs of mice. Before administration of glycerol, mice must be deprived of water for about 24 h. After intramuscular administration of glycerol in mice, BUN levels are significantly elevated within a few hours [30]. In SCID mice, intramuscular injection of 7.5 ml/kg glycerol results in maximum elevation of BUN and serum creatinine after 24 h and remains elevated for 5 days to normalize thereafter [32].…”

Evaluations of lipid peroxidation and inflammation in short‐term glycerol‐induced acute kidney injury in rats

“…1,7,12,13 Muscle cells damaged during the process of rhabdomyolysis release immunostimulatory molecules that activate the production of pro-inflammatory cytokines such as interleukin-6 (IL-6) and tumour necrosis factor-α (TNF-α), thus leading to kidney injury. [12][13][14] In sepsis-induced AKI, TNF-α activates inducible nitric oxide synthase (iNOS), an indicator of inflammation and stress, which lead to excessive nitric oxide (NO) production. 15,16 The overproduction of iNOS-derived NO causes kidney tubular injury in glycerol-induced AKI.…”