The increasing emergence of multidrug-resistant (MDR) bacteria has been recognized as a public health threat worldwide. Hospitalized patients and outpatients are commonly infected by non-fermenting Gram-negative bacilli (NFGNB), particularly the Acinetobacter calcoaceticus-Acinetobacter baumannii complex (ACB) and Pseudomonas aeruginosa. Antimicrobial agents are critical for treating the nosocomial infections caused by NFGNB. The aim of this study was to assess antimicrobial resistance and the use of antimicrobial agents. The bacterial isolates of 638,152 specimens from both inpatients and outpatients, retrieved from 2001 to 2008 at a medical center in central Taiwan, were examined for their susceptibility to various antimicrobial agents, including cefepime, imipenem, ciprofloxacin, gentamicin, amikacin, meropenem, and levofloxacin. Administrated prescriptions of the monitored antibiotics were analyzed using the Taiwan National Health Insurance Research Database (NHIRD). Our results show that the defined daily doses (DDDs) for cefepime, imipenem, and ciprofloxacin increased with time, and a trend toward reduced antimicrobial sensitivities of both ACB and P. aeruginosa was noticeable. In conclusion, the antimicrobial sensitivities of ACB and P. aeruginosa were reduced with the increased use of antibiotics. Continuous surveillance of antibiotic prescriptions and the prevalence of emerging resistance in nosocomial infections is warranted.

Background: Inhibition of HIF-prolyl hydroxylase (PHD) has been shown to protect against various kidney diseases. However, there are controversial reports on the effect of PHD inhibition in renoprotection. The present study determined whether delivery of PHD2 siRNA using a siRNA carrier, folic acid (FA)-decorated polyamidoamine dendrimer generation 5 (G5-FA), would mainly target kidneys and protect against renal ischemia/reperfusion injury (I/R). Methods:The renal I/R was generated by clipping the renal pedicle for 30 minutes in uninephrectomized mice. Mice were sacrificed 48 hours after I/R. Normal saline or G5-FA complexed with control or PHD2 siRNA was injected via tail vein 24 h before ischemia.Results: After the injection of near-infrared fluorescent dye-labeled G5-FA, the fluorescence was mainly detected in kidneys, but not in other organs. The reduction of PHD2 mRNA and protein was only observed in kidneys but not in other organs after injection of PHD2-siRNA-G5-FA complex. The injection of PHD2-siRNA-G5-FA significantly alleviated renal I/R injury, as shown by the inhibition of increases in serum creatinine and BUN, the blockade of increases in KIM-1 and NGAL and the improvement of histological damage compared with mice treated with control siRNA. Conclusion: PHD2 siRNA can be delivered specifically into kidneys using G5-FA and that local knockdown of PHD2 gene expression within the kidney alleviates renal I/R injury. Therefore, G5-FA is an efficient siRNA carrier to deliver siRNA into the kidney, and that local inhibition of PHD2 within the kidney may be a potential strategy for the management of acute I/R injury.

Cisplatin is an established chemotherapeutic drug for treatment of solid-organ cancers, and is the primary drug utilized in the treatment of head and neck cancer; however, cisplatin-induced nephrotoxicity largely limits its clinical use. Inhibition of sphingosine kinase 2 (SphK2) has been demonstrated to alleviate various kidney diseases. Therefore, we hypothesized that inhibition of SphK2 could also protect against cisplatin-induced nephrotoxicity. Results from the present study showed that the SphK2 inhibitor, ABC294640 or the knockdown of SphK2 by siRNA blocked the cisplatin-induced increase of cellular injury markers, neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule-1 (KIM-1) and Cleaved caspase-3 by Western blot analysis in HK-2 cells, a human renal tubular cell line. In addition, SphK2 inhibition blocked cisplatin-induced activation of NF-κB by Western blotting and Immunostaining analysis. Furthermore, SphK2 inhibition suppressed cisplatin-induced increases of proinflammatory markers, NLR Family Pyrin Domain Containing 3 (NLRP3), Interleukin-1β and Interleukin-6. Genetic deletion of the SphK2 gene in mice further confirmed that the inhibition of SphK2 protected against Cisplatin-induced kidney damage in vivo. Compared with wild type mice, SphK2 knockout mice exhibited less renal dysfunction and reduced promotion of kidney injury markers, inflammatory factors, tubular morphology damage, and fibrotic staining. At the same time, SphK2 inhibitor ABC294640 failed to interfere with the activity of cisplatin or radiation in two cell culture models of head and neck cancer. It is concluded that inhibition of Sphk2 protects against cisplatin-induced kidney injury. SphK2 may be used as a potential therapeutic target for the prevention or treatment of cisplatin-induced kidney injury.

Objective: We have previously reported that renal medullary sphingosine-1-phosphate (S1P) regulates sodium excretion via the S1P type-1 receptor (S1PR1). As S1PR1 is predominantly expressed in collecting ducts (CD), the present study tested the hypothesis that the CD-S1PR1 pathway plays a critical role in sodium excretion and contributes to salt-sensitive hypertension.Methods: CD-specific S1PR1 knockout mice were generated by crossing aquaporin-2-Cre mice with S1PR1floxed mice. Renal sodium excretion and arterial pressure were compared between wild type and KO mice in response to high-salt challenges and treatment of deoxycorticosterone acetate (DOCA) salt.Results: Protein levels of renal medullary S1PR1 were increased by 100% after high-salt intake, whereas DOCA treatment with high-salt intake blocked the increase of S1PR1 levels. Urinary sodium excretions in knockout mice were decreased by 60% compared with wild type mice after acute intravenous sodium loading (0.84 AE 0.16 vs. 2.22 AE 0.62 mmole/min per g kwt). The pressure natriuresis was impaired in knockout mice compared with wild type mice (4.32 AE 1.04 vs. 8.73 AE 0.19 mmole/min per g kwt).The chronic high-salt intake-induced positive sodium balance was enhanced in knockout mice compared with wild type mice (5.27 AE 0.39 vs. 2.38 AE 1.04 mmol/100 g BW per 24 h). After 10-day DOCA-salt treatment, knockout mice developed more severe hypertension than wild type mice (SBP 142 AE 8 vs. 115 AE 4 mmHg). Conclusion:The deletion of CD-S1PR1 reduced sodium excretion, promoted sodium retention, and accelerated DOCA-salt-induced salt-sensitive hypertension, suggesting that the CD-S1PR1 signaling is an important antihypertensive pathway by promoting sodium excretion and that impairment of renal medullary S1PR1 may represent a novel mechanism for salt-sensitive hypertension.

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Blackfoot disease (BFD) is a peripheral arterial occlusive disease found among human inhabitants along the southwest coast of Taiwan. Well water used for drinking and cooking contains humic acid (HA), which may be a possible etiological factor. In this study, HA toxicity was investigated in human erythrocytes and was found to induce echinocytic formation. Morphological changes occurred in both a concentration- and time-dependent fashion. The presence of HA was also observed to facilitate the loading of erythrocytes with excess Ca(2+) (1 mM), which may have occurred following permeability changes in cell membranes, leading to echinocytic transformations. Sodium dodecyl sulfate (SDS) gel electrophoresis indicated that echinocyte formation was due to the oxidation of normal membrane proteins that were replaced by high-molecular-weight proteins. Humic acid also induced hemoglobin oxidation in erythrocytes. Data show that oxidative stress generated by HA as well as direct effects were exerted on the cytoskeleton of erythrocytes, and these may be significant factors in the etiology of BFD.

Renal fibrosis is a typical characteristic of progressive chronic kidney disease (CKD). Current treatment options to slow renal fibrosis are still very limited. Endocannabinoids known as anandamide and 2‐arachidonoylglycerol play a critical role in regulating renal physiology via cannabinoid receptors (CB1 and CB2). Fatty acid amide hydrolase (FAAH) is one of the major enzymes to metabolize endocannabinoids. Studies have shown that endocannabinoid system is present in the kidney and that CB1 and CB2 are involved in CKD. However, the role of FAAH in CKD remains unclear. The present study tested the hypothesis that FAAH pathway participates in the kidney damage in post ischemia‐reperfusion (PIR) model, which produces chronic renal injury and fibrosis, using FAAH knockout mice. Male wild type C57BL6 (WT) and Faah−/− mice were subjected to PIR by unilateral ischemia‐reperfusion and contralateral nephrectomy 10 days after ischemia‐reperfusion. Compared with WT mice, Faah−/− mice showed significantly reduced BUN (mean: 22.0 ± 1.16, 102.0± 9.50, and 61± 4.35 mg/dL in WT‐shame, WT‐PIR, and Faah−/−‐PIR mice, respectively, p<0.05) and plasma creatinine level (mean: 0.18 ± 0.02, 1.18 ± 0.06, and, 0.54± 0.05 mg/dL in WT‐shame, WT‐PIR, and Faah−/−‐PIR mice, respectively, p<0.05) in response to PIR. Western blot analysis showed that increased expression of fibrotic protein alpha‐smooth muscle actin in the kidneys were significantly reduced in Faah−/− mice, whereas remained high in WT mice under PIR (1.85‐fold versus 2.46‐fold, p<0.05). Collagen staining by Sirius Red showed the same pattern as alpha‐smooth muscle actin expression in the kidneys from different groups of mice. Histological evaluation by Periodic acid–Schiff (PAS) staining showed that Faah−/− mice exhibited less tissue damage especially in tubular structure in response to PIR compared with WT mice. These results suggest that inhibition of FAAH may preserve renal function and prevent renal fibrosis and that FAAH may serve as a target for developing novel and effective treatment for CKD. Support or Funding Information NIH grants R01DK54927, R01DK107991, R01HL145163

Sphingosine‐1‐phosphate (S1P) is a bioactive sphingolipid metabolite and shown to participate in various kidney diseases. S1P is produced by sphingosine kinases (Sphks), which phosphorylate sphingosine into S1P. It has been demonstrated that knockout of Sphk2 gene protects the kidneys in unilateral ureteral obstruction model. The present study tested the hypothesis that inhibition of Sphk2 protects the kidneys against cisplatin‐induced nephrotoxicity. Male C57BL6 mice were divided into three groups: vehicle (Ctrl), cisplatin + vehicle (Cis) and cisplatin + ABC294640, a Sphk2 inhibitor (Cis + in). Cisplatin (10 mg/Kg) was given by weekly i.p. injection and Sphk2 inhibitor (35 mg/Kg) gavage every other day for 4 weeks. Plasma creatinine levels were significantly higher in Cis group than that in Ctrl, whereas it was significantly lower in Cis+in group than that in Cis (mean: 0.17 ± 0.02, 0.38 ± 0.05, and 0.20 ± 0.02 mg/dL in Ctrl, Cis and Cis+in group, respectively, p<0.05). Western blot analysis showed that the levels of fibrotic protein alpha‐smooth muscle actin (α‐SMA) in the kidneys were significantly increased in Cis group and that this increase in α‐SMA was blocked in Cis+in group. The relative α‐SMA protein levels were 1.0 ± 0.04, 1.8 ± 0.11 and 0.8 ± 0.19 in Ctrl, Cis and Cis+in group, respectively (p<0.05). The increased level of Kidney Injury Molecule‐1 was also significantly reduced in Cis+in group compared with that in Cis group. These results suggest that Sphk2 pathway mediates cisplatin‐induced kidney damage. Manipulating Sphk2 may be used as a therapeutic strategy in the management of cisplatin‐induced nephrotoxicity. Support or Funding Information NIH grants R01DK54927, R01DK107991, R01HL145163