Rat Model Of Acute Kidney Injury Research Articles

Targeted Delivery of Bone Mesenchymal Stem Cells by Ultrasound Destruction of Microbubbles Promotes Kidney Recovery in Acute Kidney Injury

The aim of the present study was to explore whether ultrasound microbubble destruction augments site-targeted engraftment of bone marrow mesenchymal stem cells (BM-MSCs) to kidney tissue and promotes recovery of the kidney in acute kidney injury (AKI) in rats. AKI was induced by the subcutaneous injection of mercuric chloride (HgCl2). Forty Sprague-Dawley (SD) rats were randomly divided into the following groups after the establishment of rat models of AKI (n = 10): (1) Model group alone (control group); (2) 1.0 W/cm2 ultrasound (US) + microbubble (MB) (US/MB group); (3) MSCs group; and (4) 1.0 W/cm2 US+MB + MSCs group (US/MB + MSCs group). The number of 4′,6-diamidino-2-phenylindole (DAPI) labelled MSCs was evaluated by fluorescence microscopy and real-time polymerase chain reaction (RT-PCR) and Western blotting and histological examination were performed 7 days after MSCs transplantation. It was observed via fluorescence microscopy that the number of DAPI-labelled MSCs in the kidney for the US/MB + MSCs group was significantly more than the MSCs group (p < 0.05). The results from RT-PCR revealed that the US/MB and US/MB + MSCs groups markedly increased the level of inter-cellular adhesion molecule 1 (ICAM-1) messenger ribonucleic acid (mRNA) compared with the control group and the MSCs group (p < 0.05). Western blot analysis showed that the expression of hepatocyte growth factor (HGF) and epidermal growth factor (EGF) in the US/MB + MSCs group were markedly increased compared with the all other groups (p < 0.01). The extent of tubular necrosis and dilation was significantly milder in the US/MB + MSCs group (acoustic exposure conditions: 5s at 1 MHz and 1.0 W/cm2 with a 5s pause, totalling 60 s) than the all other groups (p < 0.05). Microbubble destruction by 1.0 W/cm2 ultrasound can promote both the homing of BM-MSCs to kidney tissue and the recovery of the kidney in AKI in rats.

The tubule pathology of septic acute kidney injury: a neglected area of research comes of age

Oxidant stress and compromised microcirculation underlie renal pathophysiology in septic acute kidney injury (AKI). Holthoff et al. report that resveratrol ameliorates these coupled abnormalities. They did not establish the primacy of either defect in septic AKI. However, tubule mitochondrial defects were recently reported to be involved in septic AKI pathogenesis, and resveratrol targets PGC-1α and respiratory enzymes. Together, these findings open new avenues for research into long-unresolved issues in the pathophysiology of septic AKI.

Hepatocyte Growth Factor Modification Promotes the Amelioration Effects of Human Umbilical Cord Mesenchymal Stem Cells on Rat Acute Kidney Injury

Human umbilical cord-derived mesenchymal stem cells (hucMSCs) are particularly attractive cells for cellular and gene therapy in acute kidney injury (AKI). Adenovirus-mediated gene therapy has been limited by immune reaction and target genes selection. However, in the present study, we investigated the therapeutic effects of hepatocyte growth factor modified hucMSCs (HGF-hucMSCs) in ischemia/reperfusion-induced AKI rat models. In vivo animal models were generated by subjecting to 60 min of bilateral renal injury by clamping the renal pedicles and then introduced HGF-hucMSCs via the left carotid artery. Our results revealed that serum creatinine and urea nitrogen levels decreased to the baseline more quickly in HGF-hucMSCs-treated group than that in hucMSCs- or green fluorescent protein-hucMSCs-treated groups at 72 h after injury. The percent of proliferating cell nuclear antigen-positive cells in HGF-hucMSCs-treated group was higher than that in the hucMSCs or green fluorescent protein-hucMSCs-treated groups. Moreover, injured renal tissues treated with HGF-hucMSCs also exhibited less hyperemia and renal tubule cast during the recovery process. Immunohistochemistry and living body imaging confirmed that HGF-hucMSCs localize to areas of renal injury. Real-time polymerase chain reaction result showed that HGF-hucMSCs also inhibited caspase-3 and interleukin-1β mRNA expression in injured renal tissues. Western blot also showed HGF-hucMSCs-treated groups had lower expression of interleukin-1β. Terminal deoxynucleotidyl transferase biotin-deoxyuridine triphosphate (dUTP) nick end labeling method indicated that HGF-hucMSCs-treated group had the least apoptosis cells. In conclusion, our findings suggest that HGF modification promotes the amelioration of ischemia/reperfusion-induced rat renal injury via antiapoptotic and antiinflammatory mechanisms; thus, providing a novel therapeutic application for hucMSCs in AKI.

Glutamine attenuates tubular cell apoptosis in acute kidney injury via inhibition of the c-Jun N-terminal kinase phosphorylation of 14-3-3*

Tubular cell apoptosis is linked to the development of acute kidney injury (AKI), which is a frequent complication of traumatic rhabdomyolysis. The 14-3-3 protein, a multifunctional regulatory protein, binds a variety of apoptotic proteins and is a target of c-Jun N-terminal kinase (JNK) in the cell death signaling pathway. Therefore, we examined whether JNK phosphorylates 14-3-3 and downstream mitochondrial death pathway mediates apoptosis in myoglobinuric acute kidney injury to determine whether these events are regulated by glutamine, which is known to induce heat shock protein 70 (Hsp70), or involved in the synthesis of glutathione (GSH). A prospective, randomized, controlled animal trial. University research laboratory. Male Sprague-Dawley rats. We utilized a rat model of myoglobinuric AKI. Glutamine or saline was administered intraperitoneally before and after glycerol injection. Apoptotic cell death was determined via transferase-mediated deoxyuridine triphosphate nick-end labeling staining, and Hsp70, JNK, phospho-JNK, 14-3-3, phospho-14-3-3, and many other apoptotic proteins were examined via Western blot. Relative interactions between these proteins were tested by coimmunoprecipitation analyses. Also, GSH levels were determined to further test whether glutamine affects apoptotic cell death in myoglobinuric AKI. Glutamine treatment elevated levels of Hsp70 or reduced GSH and attenuated tubular cell apoptosis in kidney tissues of rats with myoglobinuric AKI. Further, Hsp70 physically associated with JNK, thereby limiting its activation. In addition, JNK evidently interacted with 14-3-3, leading to its phosphorylation, Bad or Bax dissociation from 14-3-3, and subsequent Bax mitochondrial translocation and caspase activation in rats with acute renal failure. Glutamine treatment very modestly lowered elevated levels of serum creatinine in AKI rats. A signaling link between JNK and 14-3-3 and subsequent mitochondrial death pathway may partly act as an early signaling that promotes apoptotic cell death leading to AKI, and glutamine may at least partially prevent apoptosis via enhancing Hsp70 or GSH levels.

CELL THERAPY USING MULTIPOTENT MARROW STROMAL CELLS IS A PROMISING NEW TREATMENT APPROACH FOR ACUTE KIDNEY INJURY.

Acute kidney injury (AKI) is a serious clinical entity, and no specific treatment is currently available. Stem cell therapy has been shown to be a promising multimodal approach directed at different pathophysiologic aspects of AKI. Bone marrow-derived mesenchymal stem cells provide a promising therapeutic perspective due to their immunomodulatory and antiapoptotic properties and the secretion of various growth factors. However, the optimal dosing regimen and source of multipotent marrow stromal cells (MSCs) are currently unknown. Here we tested both the early renoprotective potential and the long-term contribution of various doses (0.5/2/5 × 106) of allogeneic and syngeneic MSCs in a rat model of ischemic AKI. MSC from human placental alkaline phosphatase (hPAP) transgenic Fischer rats were used in an allogeneic and syngeneic setting. Postreflow administration of hPAP + MSCs from Fischer to Sprague-Dawley rats with severe AKI improved both recovery of renal function on days 1 and 3 after AKI, with the lowest dose being the most protective. In an autologous setting, MSCs improved recovery after AKI in a dose-dependent fashion, but there was no difference between 2 and 5 × 106 MSCs administered. After 3 months creatinine clearance was better preserved in MSC-treated animals (2.1) versus controls (1.5 mL/min), whereas there were no differences in blood pressure, hematocrit, and weight. Compared with controls, MSC-treated animals had a lower renal fibrosis score (1.8 vs 2.3), and renal TGF-β and PAI-1 mRNA levels were significantly down-regulated. hPAP + MSCs could not be detected in kidneys, brain, liver, lung, and spleen by highly sensitive PCR, whereas the bone marrow in 3 of 6 animals was positive for hPAP, suggesting low-level engraftment. We conclude that allogeneic MSCs enhance early recovery from AKI as well as isogeneic cells and appear safe in the long term. They do not contribute to significant replacement of renal cell types, while ameliorating both long-term fibrotic changes and loss in renal function after AKI.