Differential gene expression following early renal ischemia/reperfusion

Supavekin, Suroj; Zhang, Weijia; Kucherlapati, Raju; Kaskel, Frederick J.; Moore, Leon C.; Devarajan, Prasad

doi:10.1046/j.1523-1755.2003.00928.x

Cited by 412 publications

(311 citation statements)

References 47 publications

(17 reference statements)

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“…It is considered a specific marker of neutrophil activity and a strong bacteriostatic agent, as it involves the antibacterial iron-depletion strategy of the innate immune system (13,26). NGAL is expressed at low levels in normal organs and increases in injured epithelia, including in the lung, colon, and especially in the kidney (11,27,28). The levels of NGAL are not raised in healthy full-term newborns at birth, but neutrophils from newborns, even premature infants, have been able to rapidly release NGAL upon bacterial or fungal stimulation in vivo (15).…”

Section: Discussionmentioning

confidence: 99%

Plasma neutrophil gelatinase-associated lipocalin predicts acute pyelonephritis in children with urinary tract infections

et al. 2015

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Background:The identification of acute pyelonephritis (APN) is still a challenge. Methods: Patients admitted for their first urinary tract infection (UTI) were enrolled. Plasma neutrophil gelatinaseassociated lipocalin (NGAL) levels were measured at admittance and after treatment. Laboratory, clinical, and imaging results were compared between children with and without APN. results: A total of 123 patients were enrolled (53 APN and 70 lower UTI). After adjusting for age and gender, plasma NGAL levels were higher in the APN group than in the lower UTI group (233 (129-496) ng/ml vs. 71 (50.8-110) ng/ml, P < 0.001). NGAL levels were correlated with the serum levels of leukocytes, C-reactive protein, and creatinine, as well as fever duration (P < 0.05). Multivariable analysis revealed that logtransformed plasma NGAL was an independent predictor of APN (P < 0.05). Receiver operating curve analysis showed a good diagnostic profile of NGAL for identifying APN (area under the curve 0.864) with a best cut-off value of 102.5 ng/ml. The NGAL levels in both two groups decreased after treatment compared to levels before treatment (P < 0.001). conclusion: Plasma NGAL can be a sensitive predictor for identifying APN and monitoring the treatment response of pediatric UTI. u rinary tract infections (UTIs) are among the most common bacterial infections in children (1). Early detection and proper management of UTIs is important since UTIs involving the kidney may cause permanent renal scarring and be a risk factor for future development of renal insufficiency (2). Establishing the diagnosis of acute pyelonephritis (APN) requires imaging with 99m Tc-dimercaptosuccinic acid (DMSA) scintigraphy to view renal parenchymal involvement (3). Although a DMSA scan is considered to be very sensitive in the assessment of renal damage, it is expensive, not readily available in all centers, and exposes the patients to radiation (4). Therefore, a more practical and accessible tool to determine the presence of renal parenchymal involvement could be helpful for the timely management of UTIs.Neutrophil gelatinase-associated lipocalin (NGAL), as a member of the lipocalin superfamily, is produced from the nephron in response to tubular epithelial damage (5). It has been identified as one of the earliest and potentially one of the most indicative biomarkers of acute kidney injury (AKI) from a diverse array of conditions and can differentiate between prerenal and intrinsic causes (6,7). Urinary NGAL (uNGAL) levels increase in patients with different causes of nephropathies (8,9) and might be a valuable tool in monitoring the treatment response of various renal diseases (10,11).As an iron-carrier protein derived from human neutrophils, NGAL also plays an important role in the innate immune response to bacterial infection (12). Experimentally, NGAL was capable of blocking Escherichia coli growth under ironpoor conditions, but NGAL with siderophore iron was not (13). NGAL-knockout mice demonstrated substantially increased mortality after intraperitoneal i...

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Section: Discussionmentioning

confidence: 99%

Plasma neutrophil gelatinase-associated lipocalin predicts acute pyelonephritis in children with urinary tract infections

et al. 2015

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“…We used well established murine models in which the structural and functional consequences of brief periods of renal ischemia have been previously documented (27)(28)(29)(30). Briefly, male Swiss-Webster mice (Taconic Farms, Germantown, NY) weighing 25 to 35 g were housed with a 12:12 h light:dark cycle and were allowed free access to food and water.…”

Section: Mouse Model Of Renal Ischemia-reperfusion Injurymentioning

confidence: 99%

“…Slides were then incubated with secondary antibodies conjugated with either Cy5 (for Fas) or Cy3 (for ankyrin) and visualized with rhodamine or fluorescein filters, respectively. For colocalization of Fas with apoptotic cells, serial sections were subjected to either the TUNEL assay or to immunohistochemistry as described previously (28,29). Visualization with rhodamine filters revealed cells that stained positive for Fas, and examination with fluorescein filters identified TUNEL-positive nuclei in serial sections.…”

Section: Colocalization In Vivomentioning

confidence: 99%

The Death Domain of Kidney Ankyrin Interacts with Fas and Promotes Fas-Mediated Cell Death in Renal Epithelia

Río¹,

Imam²,

DeLeon³

et al. 2004

Journal of the American Society of Nephrology

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Abstract. Ankyrins are a ubiquitously expressed family of conserved proteins that mediate the linkage of integral membrane proteins such as transporters and channels with the underlying cytoskeleton. Ankyrins possess a conserved death domain, the functional significance of which has remained puzzling. In this study, the death domain of AnkG190, the isoform of ankyrin expressed in kidney tubules, was used as bait in a yeast two-hybrid screen to identify interacting partners. One of these interactions was with the proapoptotic molecule Fas. This was confirmed by coimmunoprecipitation, colocalization, and glutathione S-transferase pull-down assays in cultured renal epithelial (MDCK) cells. Site-directed mutagenesis of a conserved arginine (R1496 in AnkG190), previously shown to be critical for the binding of Fas (R234 in Fas) to FADD, abolished the interaction of ankyrin's death domain with Fas. Overexpression of constructs containing ankyrin's death domain promoted Fas-mediated apoptosis in MDCK cells. The linkage between ankyrin and Fas was confirmed in vivo in mouse kidney tubule cells by coimmunoprecipitation and colocalization. In an established mouse model of renal ischemia-reperfusion injury characterized by apoptotic tubule cell death, the expression of both ankyrin and Fas was markedly induced, and the interaction between these molecules remained intact. The results identify a novel tethering interaction between ankyrin and Fas in kidney epithelia and suggest that AnkG190 may play a role as an adapter molecule in renal tubule cell death.Tethering interactions between membrane proteins and the underlying spectrin-based cytoskeleton play key roles in several cellular activities, including organization of plasma membrane domains (1

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“…To date, broad molecular characterization of AKI models has largely focused on transcriptional profiling of organ-wide signatures (10)(11)(12)(13)(14)(15). Several promising biomarkers have emerged from these studies (16,17).…”

Section: Introductionmentioning

confidence: 99%

Cell-specific translational profiling in acute kidney injury

et al. 2014

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Acute kidney injury (AKI) promotes an abrupt loss of kidney function that results in substantial morbidity and mortality. Considerable effort has gone toward identification of diagnostic biomarkers and analysis of AKI-associated molecular events; however, most studies have adopted organ-wide approaches and have not elucidated the interplay among different cell types involved in AKI pathophysiology. To better characterize AKI-associated molecular and cellular events, we developed a mouse line that enables the identification of translational profiles in specific cell types. This strategy relies on CRE recombinase-dependent activation of an EGFP-tagged L10a ribosomal protein subunit, which allows translating ribosome affinity purification (TRAP) of mRNA populations in CRE-expressing cells. Combining this mouse line with cell type-specific CRE-driver lines, we identified distinct cellular responses in an ischemia reperfusion injury (IRI) model of AKI. Twenty-four hours following IRI, distinct translational signatures were identified in the nephron, kidney interstitial cell populations, vascular endothelium, and macrophages/monocytes. Furthermore, TRAP captured known IRI-associated markers, validating this approach. Biological function annotation, canonical pathway analysis, and in situ analysis of identified response genes provided insight into cell-specific injury signatures. Our study provides a deep, cell-based view of early injury-associated molecular events in AKI and documents a versatile, genetic tool to monitor cell-specific and temporal-specific biological processes in disease modeling.

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Differential gene expression following early renal ischemia/reperfusion

Cited by 412 publications

References 47 publications

Plasma neutrophil gelatinase-associated lipocalin predicts acute pyelonephritis in children with urinary tract infections

Plasma neutrophil gelatinase-associated lipocalin predicts acute pyelonephritis in children with urinary tract infections

The Death Domain of Kidney Ankyrin Interacts with Fas and Promotes Fas-Mediated Cell Death in Renal Epithelia

Cell-specific translational profiling in acute kidney injury

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