Recent studies have described that the Notch signaling pathway is activated in a wide range of renal diseases. Angiotensin II (AngII) plays a key role in the progression of kidney diseases. AngII contributes to renal fibrosis by upregulation of profibrotic factors, induction of epithelial mesenchymal transition and accumulation of extracellular matrix proteins. In cultured human tubular epithelial cells the Notch activation by transforming growth factor-β1 (TGF-β1) has been involved in epithelial mesenchymal transition. AngII mimics many profibrotic actions of TGF-β1. For these reasons, our aim was to investigate whether AngII could regulate the Notch/Jagged system in the kidney, and its potential role in AngII-induced responses. In cultured human tubular epithelial cells, TGF-β1, but not AngII, increased the Notch pathway-related gene expression, Jagged-1 synthesis, and caused nuclear translocation of the activated Notch. In podocytes and renal fibroblasts, AngII did not modulate the Notch pathway. In tubular epithelial cells, pharmacological Notch inhibition did not modify AngII-induced changes in epithelial mesenchymal markers, profibrotic factors and extracellular matrix proteins. Systemic infusion of AngII into rats for 2 weeks caused tubulointerstitial fibrosis, but did not upregulate renal expression of activated Notch-1 or Jagged-1, as observed in spontaneously hypertensive rats. Moreover, the Notch/Jagged system was not modulated by AngII type I receptor blockade in the model of unilateral ureteral obstruction in mice. These data clearly indicate that AngII does not regulate the Notch/Jagged signaling system in the kidney, in vivo and in vitro. Our findings showing that the Notch pathway is not involved in AngII-induced fibrosis could provide important information to understand the complex role of Notch system in the regulation of renal regeneration vs damage progression.
The aim of this study was to evaluate the effect of Gd-chelate on renal function, iron parameters and oxidative stress in rats with CRF and a possible protective effect of the antioxidant N-Acetylcysteine (NAC). Male Wistar rats were submitted to 5/6 nephrectomy (Nx) to induced CRF. An ionic-cyclic Gd (Gadoterate Meglumine) was administrated (1.5 mM/KgBW, intravenously) 21 days after Nx. Clearance studies were performed in 4 groups of anesthetized animals 48 hours following Gd- chelate administration: 1–Nx (n = 7); 2–Nx+NAC (n = 6); 3–Nx+Gd (n = 7); 4–Nx+NAC+Gd (4.8 g/L in drinking water), initiated 2 days before Gd-chelate administration and maintained during 4 days (n = 6). This group was compared with a control. We measured glomerular filtration rate, GFR (inulin clearance, ml/min/kg BW), proteinuria (mg/24 hs), serum iron (µg/dL); serum ferritin (ng/mL); transferrin saturation (%), TIBC (µg/dL) and TBARS (nmles/ml). Normal rats treated with the same dose of Gd-chelate presented similar GFR and proteinuria when compared with normal controls, indicating that at this dose Gd-chelate is not nephrotoxic to normal rats. Gd-chelate administration to Nx-rats results in a decrease of GFR and increased proteinuria associated with a decrease in TIBC, elevation of ferritin serum levels, transferrin oversaturation and plasmatic TBARS compared with Nx-rats. The prophylactic treatment with NAC reversed the decrease in GFR and the increase in proteinuria and all alterations in iron parameters and TBARS induced by Gd-chelate. NAC administration to Nx rat did not modify the inulin clearance and iron kinetics, indicating that the ameliorating effect of NAC was specific to Gd-chelate. These results suggest that NAC can prevent Gd-chelate nephrotoxicity in patients with chronic renal failure.
Patients with end stage renal disease often fail to follow prescribed dietary and fluid regimen, leading to undesirable outcomes. This study aimed to examine and identify factors influencing dietary, fluid, medication and dialysis compliance behaviours in patients undergoing hemodialysis.
Acute kidney injury (AKI) is a common consequence of systemic illness or injury and it complicates several forms of major surgery. Two major difficulties have hampered progress in AKI research and clinical management. AKI is difficult to detect early and its pathogenesis is still poorly understood. We recently reported results from multi-center studies where two urinary markers of cell-cycle arrest, tissue inhibitor of metalloproteinases-2 (TIMP-2) and insulin-like growth factor-binding protein 7 (IGFBP7) were validated for development of AKI well ahead of clinical manifestations-azotemia and oliguria. Cell-cycle arrest is known to be involved in the pathogenesis of AKI and this ‘dark side’ may also involve progression to chronic kidney disease. However, cell-cycle arrest has a ‘light side’ as well, since this mechanism can protect cells from the disastrous consequences of entering cell division with damaged DNA or insufficient bioenergetic resources during injury or stress. Whether we can use the light side to help prevent AKI remains to be seen, but there is already evidence that cell-cycle arrest biomarkers are indicators of both sides of this complex physiology.
Alport syndrome is a hereditary glomerulopathy with proteinuria and nephritis caused by defects in genes encoding type IV collagen in the glomerular basement membrane. All male and most female patients develop end-stage renal disease. Effective treatment to stop or decelerate the progression of proteinuria and nephritis is still under investigation. Here we showed that combination treatment of mild electrical stress (MES) and heat stress (HS) ameliorated progressive proteinuria and renal injury in mouse model of Alport syndrome. The expressions of kidney injury marker neutrophil gelatinase-associated lipocalin and pro-inflammatory cytokines interleukin-6, tumor necrosis factor-α and interleukin-1β were suppressed by MES+HS treatment. The anti-proteinuric effect of MES+HS treatment is mediated by podocytic activation of phosphatidylinositol 3-OH kinase (PI3K)-Akt and heat shock protein 72 (Hsp72)-dependent pathways in vitro and in vivo. The anti-inflammatory effect of MES+HS was mediated by glomerular activation of c-jun NH(2)-terminal kinase ½ (JNK1/2) and p38-dependent pathways ex vivo. Collectively, our studies show that combination treatment of MES and HS confers anti-proteinuric and anti-inflammatory effects on Alport mice likely through the activation of multiple signaling pathways including PI3K-Akt, Hsp72, JNK1/2, and p38 pathways, providing a novel candidate therapeutic strategy to decelerate the progression of patho-phenotypes in Alport syndrome.
To assess the risk of medication errors in subjects with renal impairment (defined as an estimated glomerular filtration rate (eGFR) ≤40 ml/min/1.73 m(2)) and the effectiveness of automatic eGFR ≤40-alerts relayed to community pharmacists.
BACKGROUND: Renal scintigraphy using 99mTc-mercaptoacetyltriglycine (99mTc-MAG3) is widely used for the assessment of renal function in humans. However, the application of this method to animal models of renal disease is currently limited, especially in rodents. Here, we have applied 99mTc-MAG3 renal scintigraphy to a mouse model of unilateral ureteral obstruction (UUO) and evaluated its utility in studying obstructive renal disease. METHODS: UUO mice were generated by complete ligation of the left ureter. Sham-operated mice were used as a control. Renal function was investigated on days 0, 1, 3, and 6 post-surgery using dynamic planar imaging of 99mTc-MAG3 activity following retro-orbital injection. Time-activity curves (TACs) were produced for individual kidneys and renal function was assessed by 1) the slope of initial 99mTc-MAG3 uptake (SIU), which is related to renal perfusion; 2) peak activity; and 3) the time-to-peak (TTP). The parameters of tubular excretion were not evaluated in this study as 99mTc-MAG3 is not excreted from UUO kidneys. RESULTS: Compared to sham-operated mice, SIU was remarkably (>60%) reduced in UUO kidneys at day 1 post surgery and the TACs plateaued, indicating that 99mTc-MAG3 is not excreted in these kidneys. The plateau activity in UUO kidneys was relatively low (~40% of sham kidney’s peak activity) as early as day1 post surgery, demonstrating that uptake of 99mTc-MAG3 is rapidly reduced in UUO kidneys. The time to plateau in UUO kidneys exceeded 200 sec, suggesting that 99mTc-MAG3 is slowly up-taken in these kidneys. These changes advanced as the disease progressed. SIU, peak activity and TTPs were minimally changed in contra-lateral kidneys during the study period. CONCLUSIONS: Our data demonstrate that renal uptake of 99mTc-MAG3 is remarkably and rapidly reduced in UUO kidneys, while the changes are minimal in contra-lateral kidneys. The parametric analysis of TACs suggested that renal perfusion as well as tubular uptake is reduced in UUO kidneys. This imaging technique should allow non-invasive assessments of UUO renal injury and enable a more rapid interrogation of novel therapeutic agents and protocols.
Prolonged hypothermic storage causes ischemia-reperfusion injury (IRI) in the renal graft, which is considered to contribute to the occurrence of the delayed graft function (DGF) and chronic graft failure. Strategies are required to protect the graft and to prolong renal graft survival. We demonstrated that xenon exposure to human proximal tubular cells (HK-2) led to activation of range of protective proteins. Xenon treatment prior to or after hypothermia-hypoxia challenge stabilized the HK-2 cellular structure, diminished cytoplasmic translocation of high-mobility group box (HMGB) 1 and suppressed NF-κB activation. In the syngeneic Lewis-to-Lewis rat model of kidney transplantation, xenon exposure to donors before graft retrieval or to recipients after engraftment decreased caspase-3 expression, localized HMGB-1 within nuclei and prevented TLR-4/NF-κB activation in tubular cells; serum pro-inflammatory cytokines IL-1β, IL-6 and TNF-α were reduced and renal function was preserved. Xenon treatment of graft donors or of recipients prolonged renal graft survival following IRI in both Lewis-to-Lewis isografts and Fischer-to-Lewis allografts. Xenon induced cell survival or graft functional recovery was abolished by HIF-1α siRNA. Our data suggest that xenon treatment attenuates DGF and enhances graft survival. This approach could be translated into clinical practice leading to a considerable improvement in long-term graft survival.
This study took a retrospective approach to investigate patients with catheter-associated urinary tract infection (CAUTI) over 2 years at a single hospital’s intensive care unit (ICU) to identify meaningful risk factors and causative organisms.
BACKGROUND: Fibroblast growth factor 23 (FGF23) is an important hormone in the regulation of phosphate metabolism. It is unclear whether FGF23 is associated with carotid artery calcification (CAAC) in predialysis patients. The present study aimed to clarify the relationship between FGF23 and CAAC in patients with chronic kidney disease (CKD) who were not on dialysis. METHODS: One-hundred ninety-five predialysis CKD patients were enrolled in this cross-sectional study. CAAC was assessed using multidetector computed tomography, and the prevalence of CAAC was examined. Intact FGF23 was measured in each patient. The risk factors for CAAC were evaluated using a logistic regression model. RESULTS: We found CAAC in 66% of the patients. The prevalence of CAAC significantly increased across CKD stages: it was 37% in CKD stages 1–2, 58% in stage 3; 75% in stage 4, and 77% in stage 5 (p < 0.01). In multivariate analysis, smoking, diabetes mellitus and log FGF23 were each identified as risk factors for CAAC. The study population was divided in quartiles of FGF23 levels. Compared with the lowest FGF23 quartile, each subsequent quartile had a progressively higher odds ratio (OR) for CAAC, adjusted for confounders (ORs [95% confidence interval] of 2.34 [0.78 to 7.31], 5.28 [1.56 to 19.5], and 13.6 [2.92 to 74.6] for the second, third, and fourth quartiles, respectively. CONCLUSIONS: The prevalence of CAAC is increased with the decline in the kidney function. FGF23 is independently related to CAAC in patients with CKD who are not on dialysis.