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Introduction: It has been reported that rapamycin inhibited inflammation in renal interstitial diseases. We therefore hypothesized that rapamycin could attenuate inflammation in polycystic kidney disease (PKD). Methods: Han:SPRD rats were treated with rapamycin by daily gavage from 4 weeks to 12 weeks of age at the dosage of 0.5 mg/kg/day (low dose) or 1 mg/kg/day (high dose). WT9-12 human PKD cells were treated with various concentrations of rapamycin. Results: Two-kidney/total body weight ratio and cystic index in Cy/+ kidneys were significantly reduced with the treatment of low-dose rapamycin and further reduced by the treatment with high-dose rapamycin. However, the renal function of Cy/+ rats was equally improved by the treatment with either low-dose or high-dose rapamycin. The renal cell proliferation was significantly decreased in Cy/+ kidneys with the treatment of low-dose rapamycin and was further decreased with the treatment of high-dose rapamycin as examined by Ki67 staining. The phosphorylation of S6K in cystic kidneys was decreased by low-dose rapamycin and further decreased by high-dose rapamycin. Both low-dose and high-dose rapamycin treatment decreased macrophage infiltration and the expression of complement factor B (CFB), monocyte chemoattractant protein-1 (MCP-1), and tumor necrosis factor-alpha (TNF-α) to a similar level. The expression of CFB, MCP-1, and TNF-α and phosphorylation of S6K were inhibited in WT9-12 cells treated with 10 nm rapamycin at 24 h and 48 h, respectively. Moreover, the phosphorylation of Akt was not increased by 1 nm and 10 nm of rapamycin and enhanced by 1 μm rapamycin treatment. Interestingly, WT9-12 cell proliferation could be inhibited by 1 μm rapamycin. Conclusion: Low dose of rapamycin could inhibit inflammation and protect renal function in PKD. Inflammation is more sensitive than cell proliferation in response to rapamycin treatment in PKD. [ABSTRACT FROM AUTHOR]

Introduction: Cardiovascular disease is the most common cause of morbidity and mortality in patients with ESRD. In addition to phosphate overload, oxalate, a common uremic toxin, is also involved in vascular calcification in patients with ESRD. The present study investigated the role and mechanism of hyperoxalemia in vascular calcification in mice with uremia. Methods: A uremic atherosclerosis (UA) model was established by left renal excision and right renal electrocoagulation in apoE−/− mice to investigate the relationship between oxalate loading and vascular calcification. After 12 weeks, serum and vascular levels of oxalate, vascular calcification, inflammatory factors (TNF-α and IL-6), oxidative stress markers (malondialdehyde [MDA], and advanced oxidation protein products [AOPP]) were assessed in UA mice. The oral oxalate-degrading microbe Oxalobacter formigenes (O. formigenes) was used to evaluate the effect of a reduction in oxalate levels on vascular calcification. The mechanism underlying the effect of oxalate loading on vascular calcification was assessed in cultured human aortic endothelial cells (HAECs) and human aortic smooth muscle cells (HASMCs). Results: Serum oxalate levels were significantly increased in UA mice. Compared to the control mice, UA mice developed more areas of aortic calcification and showed significant increases in aortic oxalate levels and serum levels of oxidative stress markers and inflammatory factors. The correlation analysis showed that serum oxalate levels were positively correlated with the vascular oxalate levels and serum MDA, AOPP, and TNF-α levels, and negatively correlated with superoxide dismutase activity. The O. formigenes intervention decreased serum and vascular oxalate levels, while did not improve vascular calcification significantly. In addition, systemic inflammation and oxidative stress were also improved in the O. formigenes group. In vitro, high concentrations of oxalate dose-dependently increased oxidative stress and inflammatory factor expression in HAECs, but not in HASMCs. Conclusions: Our results indicated that hyperoxalemia led to the systemic inflammation and the activation of oxidative stress. The reduction in oxalate levels by O. formigenes might be a promising treatment for the prevention of oxalate deposition in calcified areas of patients with ESRD. [ABSTRACT FROM AUTHOR]

Background: The different clinical characteristics of community-acquired acute kidney injury (CA-AKI) versus hospital-acquired AKI (HA-AKI) have remained inconclusive, and thus, a meta-analysis was conducted to summarize and quantify the clinical significance distinguishing the 2 types of AKI. Methods: We identified observational studies reporting the clinical characteristics and prognosis of HA-AKI and CA-AKI. ORs and mean differences (MDs) were extracted for each outcome and the results aggregated. The primary outcome was defined as the mortality rate; renal recovery, oliguria incidence, dialysis, intensive care unit (ICU) requirement, and length of hospital stay were secondary outcomes. Results: Fifteen eligible studies involving 46,157 patients (22,791 CA-AKI patients and 23,366 HA-AKI patients) were included. Mortality was significantly lower in CA-AKI than in HA-AKI patients, with an OR of 0.43 (95% CI 0.35–0.53). The incidence of oliguria and need for ICU were also lower in CA-AKI patients (OR 0.58, 95% CI 0.38–0.88; OR 0.24, 95% CI 0.14–0.40, respectively). CA-AKI patients had a shorter hospital stay (MD –9.42, 95% CI –13.73 to –5.12). The renal recovery rate and dialysis need between CA- and HA-AKI were similar (OR 1.27, 95% CI 0.53–3.02; OR 1.05, 95% CI 0.82–1.34, respectively). Conclusions: CA-AKI showed better clinical manifestations with a lower incidence of oliguria, reduced risk of ICU treatment, and shorter hospital stay. Mortality associated with CA-AKI was lower compared with HA-AKI, indicating a better prognosis. The rate of renal recovery and need for dialysis showed no significant difference between the 2 groups. [ABSTRACT FROM AUTHOR]

Background/Aims: Autosomal dominant polycystic kidney disease (ADPKD) is the most common genetic form of kidney disease. High-throughput microarray analysis has been applied for elucidating key genes and pathways associated with ADPKD. Most genetic profiling data from ADPKD patients have been uploaded to public databases but not thoroughly analyzed. This study integrated 2 human microarray profile datasets to elucidate the potential pathways and protein-protein interactions (PPIs) involved in ADPKD via bioinformatics analysis in order to identify possible therapeutic targets. Methods: The kidney tissue microarray data of ADPKD patients and normal individuals were searched and obtained from NCBI Gene Expression Omnibus. Differentially expressed genes (DEGs) were identified, and enriched pathways and central node genes were elucidated using related websites and software according to bioinformatics analysis protocols. Seven DEGs were validated between polycystic kidney disease and control kidney samples by quantitative real-time polymerase chain reaction. Results: Two original human microarray datasets, GSE7869 and GSE35831, were integrated and thoroughly analyzed. In total, 6,422 and 1,152 DEGs were extracted from GSE7869 and GSE35831, respectively, and of these, 561 DEGs were consistent between the databases (291 upregulated genes and 270 downregulated genes). From 421 nodes, 34 central node genes were obtained from a PPI network complex of DEGs. Two significant modules were selected from the PPI network complex by using Cytotype MCODE. Most of the identified genes are involved in protein binding, extracellular region or space, platelet degranulation, mitochondrion, and metabolic pathways. Conclusions: The DEGs and related enriched pathways in ADPKD identified through this integrated bioinformatics analysis provide insights into the molecular mechanisms of ADPKD and potential therapeutic strategies. Specifically, abnormal decorin expression in different stages of ADPKD may represent a new therapeutic target in ADPKD, and regulation of metabolism and mitochondrial function in ADPKD may become a focus of future research. [ABSTRACT FROM AUTHOR]

Background/Aims: Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited kidney disorder with mutations in PKD1 or PKD2. This study aimed to identify novel PKD1 and PKD2 mutations in Chinese patients with ADPKD. Methods: Mutational analyses of both PKD genes were performed in 120 Chinese families with inherited ADPKD using long-range PCR and targeted next-generation sequencing approaches. Sanger sequencing was performed to check the positive mutations, while multiplex ligation-dependent probe amplification was adopted to examine those without mutations for the presence of large deletions. Results: A total of 93 mutations in PKD1 and PKD2 were identified in 98 Chinese families with ADPKD inheritance and the detection rate was 81.7% (98/120). The mutation rates of PKD1 and PKD2 were 91.4% (85/93) and 8.6% (85/93), respectively. Among the 93 mutations, 59.1% (55/93) were reported for the first time. A total of 65 mutations (26 nonsense, 33 frameshift, 2 large deletion, and 4 typical splicing mutations) were identified as definite pathogenic mutations. The remaining 28 mutations (21 missense, 3 in-frame deletion, and 4 atypical splicing mutations) were determined as probable pathogenic mutations. In addition, 9 de novo mutations were found by pedigree analysis. Correlation analysis between genotype and phenotype revealed that patients with PKD1 mutations or truncating mutations exhibited the most severe clinical outcome. Conclusion: The newly identified sites for known mutations will facilitate the early diagnosis and prediction of prognosis in patients with ADPKD, and provide fundamental genetic information for clinical intervention to prevent the inheritance of this disease in affected families. [ABSTRACT FROM AUTHOR]

Background/Aims: Angiotensin II (Ang II) has been regarded as an important profibrogenic cytokine in renal fibrosis. Krüppel-like factor 15 (KLF15) has been identified as an important negative transcription factor in renal fibrosis. However, little is known about the role of KLF15 in Ang II-induced renal fibrosis. Methods: In this study, we randomized mice into a control group, Ang II group or Ang II plus losartan group. KLF15 expression was examined with real-time PCR and immunofluorescence in these groups. In vitro, KLF15 expression was examined by Western blot in rat renal fibroblasts (NRK-49F) stimulated with Ang II, and the effect of altered KLF15 expression on the regulation of the profibrotic factor connective tissue growth factor (CTGF) was further explored with co-immunoprecipitation (CoIP) and chromatin immunoprecipitation (ChIP) analyses. Results: Compared with the control group, the murine model of Ang II-induced renal fibrosis demonstrated a significant decrease in renal KLF15 expression at 4 weeks and presented with progressive renal fibrosis at 6 weeks. Meanwhile, losartan, an angiotensin type 1 (AT1) receptor antagonist, effectively prevented the downregulation of KLF15 expression induced by Ang II infusion. In vitro, NRK-49F cells stimulated with Ang II exhibited a significant decrease in KLF15 expression, accompanied by a marked increase in the expression of profibrotic factors and in the production of extracellular matrix. The up-regulation of CTGF expression induced by Ang II stimulation was inhibited by KLF15 overexpression in NRK-49F cells, and losartan treatment prevented the down-regulation of KLF15 expression and the up-regulation of CTGF expression induced by Ang II stimulation. Furthermore, CoIP and ChIP assays revealed that the transcription regulator KLF15 directly bound to the co-activator P/CAF and repressed its recruitment to the CTGF promoter. Conclusions: Ang II down-regulates KLF15 expression via the AT1 receptor, and KLF15 is likely to inhibit Ang II-induced CTGF expression by repressing the recruitment of the co-activator P/ CAF to the CTGF promoter. [ABSTRACT FROM AUTHOR]

Background/Aims: Blockage of the renin-angiotensin II system (RAS) prevents or delays albuminuria in diabetic patients. The aim of this study was to investigate the inhibitory mechanism of the angiotensin receptor blocker olmesartan on albuminuria in a murine model of diabetic nephropathy. Methods: Male db/db diabetic mice were fed with placebo or 20 mg/ kg olmesartan by daily gavage for 12 weeks. Conditionally immortalized mouse podocytes were treated with glucose, angiotensin II, olmesartan or p38 inhibitor s8307 in different experimental conditions after differentiation. Results: Olmesartan reduced albuminuria in db/ db mice without change in body weight and glycemia. The increase of apoptotic cells and decrease of podocytes in the diabetic glomerulus were prevented by olmesartan. Moreover, olmesartan restored silent mating type information regulation 1 (SIRT1) expression in diabetic glomeruli. Furthermore, olmesartan treatment suppressed p38 phosphorylation but did not restore adenosine 5'-monophosphate-activated protein kinase (AMPK) phosphorylation in the diabetic glomerulus. In vitro study revealed that olmesartan prevented angiotensin II/ p38/SIRT1 induced podocyte apoptosis, but it only slightly prevented high glucose/AMPK/ SIRT1 induced podocyte apoptosis. In addition, the p38 inhibitor s8307 reversed SIRT1 expression and angiotensin II induced podocyte apoptosis. Conclusions: Olmesartan reduced albuminuria in diabetic nephropathy through inhibiting angiotensin II/p38/SIRT1 triggered podocyte apoptosis. [ABSTRACT FROM AUTHOR]

Background/Aims: Dapagliflozin (DAPA) is a selective inhibitor of the sodium-glucose cotransporter 2 (SGLT2) which induces glucosuria and osmotic diuresis. The therapeutic effect of DAPA in progressing stages of polycystic kidney disease (PKD) has not been studied. Methods: We examined the effect of DAPA in the Han: SPRD rat model of PKD. DAPA (10 mg/ kg/day) or vehicle (VEH) was administered orally via gavage to 5 week old male Han: SPRD (Cy/+) or control (+/+) rats (n = 8-9 per group) for 5 weeks. Blood and urine were collected at baseline and after 2.5 and 5 weeks of treatment to assess renal function and albuminuria. At the end of the treatment, rats were sacrificed and kidneys were excised for histological analysis. Results: After 5 weeks of treatment, DAPA-treated Cy/+ and +/+ rats exhibited significantly higher glucosuria, water intake and urine output than VEH-treated rats. DAPA-treated Cy/+ rats also exhibited significantly higher clearances for creatinine and BUN and less albuminuria than VEH-treated Cy/+ rats. DAPA treatment for 5 weeks resulted in a significant increase of the kidney weight in Cy/+ rats but no change in cyst growth. The degree of tubular epithelial cell proliferation, macrophage infiltration and interstitial fibrosis was also similar in DAPAand VEH-treated Cy/+ rats. Conclusion: The induction of glucosuria with the SGLT2-specific inhibitor DAPA was associated with improved renal function and decreased albuminuria, but had no effect on cyst growth in Cy/+ rats. Overall the beneficial effects of DAPA in this PKD model were weaker than the previously described effects of the combined SGLT1/2 inhibitor phlorizin. [ABSTRACT FROM AUTHOR]

Background/Aims: Renal interstitial fibrosis is a hallmark of progressive chronic kidney disease (CKD). Previous studies reported that kruppel-like factor 15 (KLF15) is an important regulator of cardiac fibrosis and could reduce the expression of extracellular matrix in mesangial cells. However, the role of this transcription factor in renal interstitial fibrosis has not been reported. Methods: In this study, we examined KLF15 expression in the remnant kidney of 5/6 nephrectomized rats 12 or 24 weeks after operation. In vitro we examined the effect of altered KLF15 expression on the production of extracellular matrix and the pro-fibrotic factor CTGF in rat renal fibroblasts (NRK-49F), and further explored the related mechanisms. Results: The level of KLF15 was drastically decreased in the renal interstitium of 5/6 nephrectomized rats with progressive interstitial fibrosis, especially at 24 weeks. Our in vitro evidence showed that overexpression of KLF15 repressed basal and transforming growth factor-β1 (TGF-β1)-induced extracellular matrix and CTGF in NRK-49F cells. In addition, TGF-β1-mediated activation of extracellular-regulated kinase (ERK) / mitogen-activated protein kinase (MAPK) and Jun N-terminal kinase (JNK) /MAPK downregulated KLF15 expression and increased the level of extracellular matrix and CTGF, and all these effects were completely abolished by ERK1/2 inhibitor and JNK inhibitor in NRK-49F cells. Conclusions: Our findings implicate that KLF15 plays an important role and may prove to be an antifibrotic factor in renal interstitial fibrosis through regulation of ERK/MAPK and JNK/MAPK signaling pathways. © 2014 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background: Although great progress has been made in the pathogenesis and treatment of acute kidney injury (AKI), it still has high incidence and poor prognosis. The present study was performed in order to further understand the metabolomic changes of ischemia/reperfusion (I/R)-induced AKI and the protective effect of L-carnitine on AKI. Methods: Kidney tissues and serum samples were collected at different time points from three groups of rats including control group, I/R group and L-carnitine-pretreated group. High-performance liquid chromatography coupled with mass spectrometry-based metabolomics approach was applied to investigate the characteristic of I/R-induced AKI and the protective effects of L-carnitine in rat kidney I/R model. Antioxidant enzymatic activity and phospholipase A2 activity were determined to validate the metabolic outcomes. Results: Changes in the pattern of endogenous metabolites as a result of kidney I/R injury were readily detected as early as 2 h after reperfusion, and earlier than the increase in blood urea nitrogen and serum creatinine. Twenty-eight differential endogenous metabolites were discovered and structurally identified by MSn analysis. After I/R injury, lysophospholipids, free fatty acids and nitrotyrosine significantly increased, while carnitine and acetyl-carnitine significantly decreased compared to control. Phospholipase A2 activity and malondialdehyde level also increased, while superoxide dismutase activity decreased in kidney I/R injury rats. Treatment of L-carnitine 30 min prior to reperfusion significantly relieved I/R-induced metabolomic changes. Conclusion: I/R-induced AKI could be characterized by oxidative stress and changes in lipid metabolism through metabolomic investigation, and L-carnitine treatment 30 min before reperfusion had protective effects against I/R-induced AKI. Copyright © 2012 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]