Protective effects of resveratrol on acute kidney injury in rats with sepsis.

AIM: To evaluate the protective effects of resveratrol on acute kidney injury (AKI) in septic rats. METHODS: A septic rat model was established by cecal ligation and puncture (CLP). A total of 108 male Sprague Dawley rats were randomly divided into an observation group, a 6 h resveratrol intervention group and a 12 h resveratrol intervention group. Then each group was subdivided into Sham, Sham + Res, CLP and CLP + Res groups. After surgery, the survival and morphological changes in kidney tissues were observed. Serum creatinine and urea nitrogen levels, expression of GRP78, BiP, IRE1 and p65 in kidney tissues, and serum levels of TNF-α, IL-1ß, IL-6 and IL-10 were investigated. RESULTS: The survival rate of CLP + Res group (75.00%) significantly exceeded that of the CLP group (41.67%) (P<0.05). At postoperative 12 h, resveratrol significantly decreased serum creatinine and urea nitrogen levels (P<0.05). Resveratrol evidently relieved renal tubular swelling and luminal narrowing in CLP rats, and significantly reduced the high expressions of GRP78, BiP, phosphorylated IRE1 and p65 proteins (P<0.05). P65 was mainly located in the cytoplasm of Sham, Sham + Res and CLP + Res groups, and in the nucleus of the CLP group. At postoperative 12 h, resveratrol significantly reduced serum levels TNF-α, IL-1ß and IL-6 in CLP rats (P<0.05), whereas elevated that of IL-10 (P<0.05). CONCLUSION: Resveratrol significantly decreased the mortality rate of septic rats and alleviated AKI, probably by attenuating endoplasmic reticulum stress, inhibiting activation of the NF-κB pathway and mitigating the inflammatory response.

Knockout of interleukin-17A protects against sepsis-associated acute kidney injury.

BACKGROUND: Sepsis-associated acute kidney injury (SA-AKI) is an independent risk factor for death in patients with sepsis, but treatment for it is limited. To improve the diagnosis and treatment of SA-AKI, we must first understand its pathogenesis. Recently, interleukin (IL)-17A has been shown to be associated with the pathogenesis of acute kidney injury and sepsis, but its role in SA-AKI remains unclear. METHODS: SA-AKI was induced in male C57BL/6 and IL-17A(-/-) mice using cecal ligation and puncture (CLP) operations for 24 h. RESULTS: At 7 days, only seven mice survived in the wild-type septic group, but nine survived in the IL-17A(-/-) septic group, corresponding to survival rates of 25 % and 45 %, respectively. At 24 h after CLP operations, both wild-type and IL-17A(-/-) septic mice developed kidney injury. The IL-17A(-/-) septic mice exhibited decreased serum creatinine and blood urea nitrogen levels and an improved acute tubular necrosis score. The IL-17A(-/-) septic mice exhibited decreased IL-6, interferon-γ, tumor necrosis factor-α, CXCL1, CXCL2, and CXCL5 expression in kidney tissue, but increased IL-10 expression. In addition, renal neutrophil infiltration was attenuated significantly in the IL-17A(-/-) septic group. Moreover, IL-17A(-/-) septic mice showed significantly decreased apoptosis of tubular epithelial cells, including decreased TUNEL-positive tubular cell number and cleaved caspase-3 level, compared with the wild-type CLP group. Their Bax/Bcl-2 expression ratio was also increased. CONCLUSIONS: Our study demonstrates that IL-17A knockout could protect against SA-AKI. We show that IL-17A plays a pathogenic role in SA-AKI by increasing the levels of proinflammatory cytokines and chemokines, and by inducing neutrophil infiltration and apoptosis of tubular epithelial cells. Accordingly, IL-17A may be a novel target in SA-AKI.

Mesenchymal stem cells ameliorate sepsis-associated acute kidney injury in mice.

OBJECTIVE: Significant progress has been made in critical care medicine during the past several decades. However, the mortality rate is still high in patients with sepsis, especially with acute kidney injury (AKI). Mesenchymal stem cells (MSCs) possess an ability to ameliorate renal injury from ischemia-reperfusion, but it is still unknown whether they have the ability to reduce sepsis-associated AKI. METHODS: Male C57BL/6 mice underwent cecal ligation and puncture operation to induce sepsis and then received either normal saline or MSCs (1 × 10 cells intravenously) 3 h after surgery. RESULTS: Within 24 h after cecal ligation and puncture operation, the septic mice developed kidney injury and exhibited a higher mortality. Treatment with MSCs decreased serum creatinine and blood urea nitrogen levels and improved recovery of tubular function. mRNA levels of interleukin 6 (IL-6), IL-17, tumor necrosis factor α, interferon γ, CXCL1, CXCL2, CXCL5, CCL2, and CCL3 in kidney tissue were dramatically decreased after MSC treatment. Neutrophil infiltration in kidney and blood bacterial loads were attenuated after MSC injection. Moreover, mice treated with MSCs had a higher survival rate than the saline treatment group. Injected MSCs were mainly localized in the lungs, spleen, and abdominal cavity lymph node, but not in the kidneys. CONCLUSIONS: Treatment with MSCs can alleviate sepsis-associated AKI and improve survival in mice with polymicrobial sepsis. These effects may be mediated by the inhibition of IL-17 secretion and balance of the proinflammatory and anti-inflammatory states. Mesenchymal stem cells may be a potential new therapeutic agent for the prevention or reduction of sepsis-associated AKI.