Resveratrol improves renal microcirculation, protects the tubular epithelium, and prolongs survival in a mouse model of sepsis-induced acute kidney injury

Abstract

The mortality rate of patients who develop acute kidney injury during sepsis nearly doubles. The effectiveness of therapy is hampered because it is usually initiated only after the onset of symptoms. As renal microvascular failure during sepsis is correlated with the generation of reactive nitrogen species, the therapeutic potential of resveratrol, a polyphenol vasodilator that is also capable of scavenging reactive nitrogen species, was investigated using the cecal ligation and puncture (CLP) murine model of sepsis-induced acute kidney injury. Resveratrol when given at 5.5 h following CLP reversed the decline in cortical capillary perfusion, assessed by intravital microscopy, at 6 h in a dose-dependent manner. Resveratrol produced the greatest improvement in capillary perfusion and increased renal blood flow and the glomerular filtration rate without raising systemic pressure. A single dose at 6 h after CLP was unable to improve renal microcirculation assessed at 18 h; however, a second dose at 12 h significantly improved microcirculation and decreased the levels of reactive nitrogen species in tubules, while improving renal function. Moreover, resveratrol given at 6, 12, and 18 h significantly improved survival. Hence, resveratrol may have a dual mechanism of action to restore the renal microcirculation and scavenge reactive nitrogen species, thus protecting the tubular epithelium even when administered after the onset of sepsis.

Renal Hemodynamics in AKI

“…21,26 Similarly, rodent models of acute endotoxemia suggest that cortical peritubular capillaries are among the first renal structures injured. [27][28][29][30] Interestingly, despite an apparent full recovery of renal function at 48 hours, functional capillary density recovered only partially. 27 Moreover, areas of compromised cortical microvascular perfusion have been shown to correlate with renal tubular cell stress in corresponding regions, suggesting important links between altered peritubular microcirculation and epithelial cell dysfunction.…”

“…Oxidative stress-mediated cellular injury has been implicated in the pathogenesis of AKI as a central element of the network of danger response, affecting both endothelial and epithelial functions as well as cellular energetics. 33 Therapeutic interventions aimed at maintaining the homeostatic balance between oxygen radicals, nitric oxide, and oxygen have been shown to be effective in several studies in rodent models of septic AKI [27][28][29][30][31] and ischemia-reperfusion injury 52 as well as in large animal models of septic AKI. 53,54 The lack of effective inducible nitric oxide synthase inhibitors for clinical use can be considered an important area for research.…”

Detrimental Cross-Talk Between Sepsis and Acute Kidney Injury: New Pathogenic Mechanisms, Early Biomarkers and Targeted Therapies

“…Nevertheless, peritubular flow has been found to be sluggish and congested, probably as the result of a high capacity and low resistance circulation [9]. Other theories about the GFR decline during sepsis have focused on the reduction of filtration pressure not necessarily associated with glomerular hypoperfusion; renal and central (CVP) venous pressures are frequently increased in sepsis as a possible consequence of the so-called fluid challenge of septic patients in the first hours after ICU admission.…”

Pterostilbene attenuates acute kidney injury in septic mice

“…And it has been suggested that the in vivo biological activity of equimolar doses of Pte may be greater than that of resveratrol (6), and the antioxidant activity of Pte are superior to resveratrol due to its higher lipophilicity, which increases its ability to be absorbed compared to resveratrol (6). Studies have demonstrated that resveratrol has salutary effect on sepsis-induced multiple organ dysfunction, such as myocardial depression (7), AKI (8)(9)(10). However, the effect of Pte on sepsis-induced AKI remains unclear.…”