Acute kidney injury (AKI), which involves the loss of kidney function caused by damage to renal tubular cells, is an important public health concern. We previously showed that sirtuin (SIRT)3 protects the kidneys against mitochondrial damage by inhibiting the nucleotide-binding domain (NOD)-like receptor protein 3 (NLRP3) inflammasome, attenuating oxidative stress, and downregulating proinflammatory cytokines. In this article, we investigated the role of autophagy, mediated by a mammalian target of rapamycin (mTOR) and AMP-activated protein kinase (AMPK), in the protective effect of SIRT3, against sepsis-induced AKI, in a mouse model of cecal ligation and puncture (CLP). The AKI in CLP mice was associated with the upregulation of autophagy markers; this effect was abolished in SIRT3− mice in parallel with the downregulation of phospho (p)-AMPK and the upregulation of p-mTOR. Pretreatment with the autophagy inhibitor 3-methyladenine (3-MA) or AMPK inhibitor compound isotonic saline (C), exacerbated AKI. SIRT3 overexpression promoted autophagy, upregulated p-AMPK and downregulated p-mTOR in CLP mice, attenuating sepsis-induced AKI, tubular cell apoptosis, and inflammatory cytokine accumulation in the kidneys. The blockage of autophagy induction largely abolished the protective effect of SIRT3 in sepsis-induced AKI. These findings indicate that SIRT3 protects against CLP-induced AKI by inducing autophagy through regulation of the AMPK/mTOR pathway.
Acute kidney injury (AKI) is a rapid loss of kidney function characterized by damage to renal tubular cells driven by mitochondrial dysregulation and oxidative stress. Here, we used a murine caecal ligation and puncture (CLP) model of sepsis-induced AKI to study the role of sirtuin 3 (SIRT3), a NAD+ dependent deacetylase critical for the maintenance of mitochondrial viability, in AKI-related renal tubular cell damage and explored the underlying mechanisms. CLP induced alterations in kidney function and morphology were associated with SIRT3 downregulation, and SIRT3 deletion exacerbated CLP-induced kidney dysfunction, renal tubular cell injury and apoptosis, mitochondrial alterations, and ROS production in a knockout mouse model. SIRT3 deletion increased the CLP-induced upregulation of the NLRP3 inflammasome and apoptosis-associated speck-like protein, resulting in the activation of oxidative stress, increased production of the proinflammatory cytokines interleukin (IL)-1β and IL-18, and the enhancement of apoptosis, and these effects were reversed by antioxidant NAC. Our results suggest that SIRT3 plays a protective role against mitochondrial damage in the kidney by attenuating ROS production, inhibiting the NRLP3 inflammasome, attenuating oxidative stress, and downregulating IL-1β and IL-18.
Renal ischaemia‐reperfusion (IR) is a major cause of acute kidney injury (AKI). Cold‐inducible RNA‐binding protein (CIRBP) may contribute to AKI because its deficiency protects against renal IR injury in a mechanism believed to involve ferroptosis. We aimed to investigate whether ferroptosis is associated with CIRBP‐mediated renal damage. The differential expression of CIRBP was examined in tubular epithelial (HK2) cells during hypoxia‐reoxygenation (HR) or in response to erastin, an inducer of ferroptosis. CIRBP expression was increased in response to HR or erastin in HK2 cells but the silencing of CIRBP inhibited HR and erastin‐induced ferroptosis together with ferritinophagy. We discovered an interaction between CIRBP and ELAVL1 using STRING software, which was verified through co‐immunoprecipitation and fluorescence colocalization assays. We found that ELAVL1 is a critical regulator in the activation of ferritinophagy and the promotion of ferroptosis. HR or erastin also induced the expression of ELAVL1. An autophagy inhibitor (hydroxychloroquine) or si‐ELAVL1 transfection reversed CIRBP‐enhanced ferritinophagy activation and ferroptosis in HK2 cells under HR. Injection of anti‐CIRBP antibody into a mouse model of IR inhibited ferroptosis and decreased renal IR injury in vivo. In summary, our results provide evidence that ferritinophagy‐mediated ferroptosis could be responsible for CIRBP‐enhanced renal IR injury.
Currently, most kidneys from small pediatric deceased donors are transplanted into adult recipients (i.e., PTA). However, due to the weight mismatch, there is a high discard rate and a high ratio of EBKTs if adopting PTA. Here, we sought both to optimize utilization of these challenging but scarce donor grafts by selecting pediatric recipients and to characterize the feasibility and efficacy of this PTP allocation strategy. From February 2012 to October 2014, kidneys from 27 infant donors ≤ 15 kg were procured and distributed to 38 pediatric candidates in our center. The grafts were utilized for EBKT if the donor weighed 2.5-5 kg and for SKT if the donor weighed 5-15 kg, leading to 10 EBKTs and 28 SKTs. The overall utilization rate from small pediatric deceased donors was 94.12%. After a follow-up of 3-26 months, the graft survival rate was 89.47%, with four graft losses due to vascular thrombosis. Kidneys from low-body-weight donors should be applied to pediatric recipients, and the kidneys from infant donors ≥ 5 kg can be used in single-kidney-transplant procedures at experienced centers to optimize utilization.
Abstract. Cotyledonoid dissecting leiomyoma (CDL), also termed Sternberg tumor, is a variant of uterine leiomyoma that is rarely diagnosed by clinical evaluation. At present, ~43 cases of CDL have been reported in the literature written in the English language. Due to the distinctive grapelike gross appearance of an exophytic mass resembles placental tissue, CDL is often misdiagnosed clinically as an ovarian tumor or uterine sarcoma. Therefore, an awareness of the features of the disease is important to prevent misdiagnosis and overtreatment. The present study reports 4 cases of CDL of the uterus that were treated at the Second Hospital of Jilin University between January 2009 and December 2011. All 4 patients in the current study presented with a palpable asymptomatic pelvic mass, which was detected during physical examinations, and cancer antigen 125 tumor marker levels that were within the normal range. The exploratory laparotomy of the 4 patients revealed lobulated tumors with a grapelike appearance extending from the lateral uterine wall into the ligament or the adjacent tissues. The frozen section and postoperative pathology were diagnosed as CDL. A total abdominal hysterectomy was performed in the first case of a 55-year-old woman that had been in menopause for 7 years. The patient was well and showed no evidence of disease subsequent to 48 months of follow-up. A total abdominal hysterectomy and right salpingo-oophorectomy were performed in the second case of a 43-year-old woman, who was well and showed no evidence of disease subsequent to 26 months of follow-up. A subtotal abdominal hysterectomy and bilateral salpingectomy were performed in the third case of a 37-year-old woman, who was well and showed no evidence of disease subsequent to 27 months of follow-up. A total abdominal hysterectomy and right-salpingectomy were performed with the removal of a retroperitoneal fibroid extension in the fourth case of a 48-year-old woman, who was well and showed no evidence of disease subsequent to 32 months of follow-up.
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