Monitoring changes in gene expression in renal ischemia-reperfusion in the rat

Yoshida, Takemi; Kurella, Manjula; Beato, Francisca; Min, Hyunsuk; Ingelfinger, Julie R.; Stears, Robin L.; Swinford, Rita D.; Gullans, Steven R.; Tang, Shiow Shih

doi:10.1046/j.1523-1755.2002.00341.x

Cited by 127 publications

(85 citation statements)

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“…Attenuated UMOD expression is thus probably linked directly to the lysosomal storage process. Similar decrease in UMOD transcription and expression was found recently in mice with renal-specific inactivation of HNF1b (Gresh et al 2004), Brn1 j/j mice (Nakai et al 2003), an ischaemia-reperfusion model of ARF in rat (Yoshida et al 2002), in some patients with UAKD (Hodanova et al 2005;Vylet_al et al 2006), and in kidney damage (Chakraborty et al 2004).…”

Section: Discussionsupporting

confidence: 82%

Abnormal expression and processing of uromodulin in Fabry disease reflects tubular cell storage alteration and is reversible by enzyme replacement therapy

Vyleťal

Hůlková

Živná

et al. 2008

J of Inher Metab Disea

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Summary Uromodulin (UMOD) malfunction has been found in a range of autosomal dominant tubulointerstitial nephropathies associated with hyperuricaemia, gouty arthritis, medullary cysts and renal failure—labelled as familial juvenile hyperuricaemic nephropathy, medullary cystic disease type 2 and glomerulocystic kidney disease. To gain knowledge of the spectrum of UMOD changes in various genetic diseases with renal involvement we examined urinary UMOD excretion and found significant quantitative and qualitative changes in 15 male patients at various clinical stages of Fabry disease. In untreated patients, the changes ranged from normal to a marked decrease, or even absence of urinary UMOD. This was accompanied frequently by the presence of aberrantly processed UMOD lacking the C‐terminal part following the K432 residue. The abnormal patterns normalized in all patients on enzyme replacement therapy and in some patients on substrate reduction therapy. Immunohistochemical analysis of the affected kidney revealed abnormal UMOD localization in the thick ascending limb of Henle's loop and the distal convoluted tubule, with UMOD expression inversely proportional to the degree of storage. Our observations warrant evaluation of tubular functions in Fabry disease and suggest UMOD as a potential biochemical marker of therapeutic response of the kidney to therapy. Extended comparative studies of UMOD expression in kidney specimens obtained during individual types of therapies are therefore of great interest.

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Section: Discussionsupporting

confidence: 82%

Abnormal expression and processing of uromodulin in Fabry disease reflects tubular cell storage alteration and is reversible by enzyme replacement therapy

Vyleťal

Hůlková

Živná

et al. 2008

J of Inher Metab Disea

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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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“…In vivo, DNA fragmentation and terminal deoxynucleotidyl transferase-mediated nick end labeling (TUNEL) staining, although not wholly specific for apoptotic cell death, are significantly elevated after 2 h of reperfusion (17,18). Ischemic renal injury is associated with an increase in the expression of both the antiapoptotic Bcl-2 family of proteins, Bcl-2 and Bcl-X L , and the proapoptotic proteins Bad, p53, FADD, and Bak in the distal and proximal tubules during the first 24 h, with the net effect determining the severity of injury and dysfunction (19).…”

mentioning

confidence: 99%

Erythropoietin Protects the Kidney against the Injury and Dysfunction Caused by Ischemia-Reperfusion

Sharples

Patel²,

Brown³

et al. 2004

Journal of the American Society of Nephrology

376

289

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Abstract. Erythropoietin (EPO) is upregulated by hypoxia and causes proliferation and differentiation of erythroid progenitors in the bone marrow through inhibition of apoptosis. EPO receptors are expressed in many tissues, including the kidney. Here it is shown that a single systemic administration of EPO either preischemia or just before reperfusion prevents ischemia-reperfusion injury in the rat kidney. Specifically, EPO (300 U/kg) reduced glomerular dysfunction and tubular injury (biochemical and histologic assessment) and prevented caspase-3, -8, and -9 activation in vivo and reduced apoptotic cell death. In human (HK-2) proximal tubule epithelial cells, EPO attenuated cell death in response to oxidative stress and serum starvation. EPO reduced DNA fragmentation and prevented caspase-3 activation, with upregulation of Bcl-X L and XIAP. The antiapoptotic effects of EPO were dependent on JAK2 signaling and the phosphorylation of Akt by phosphatidylinositol 3-kinase. These findings may have major implications in the treatment of acute renal tubular damage.Erythropoietin (EPO) is the major regulator of proliferation and differentiation of erythroid progenitor cells through its antiapoptotic actions (1). EPO gene expression is under the control of the oxygen-sensitive transcription factor hypoxiainducible factor (HIF-1), which consists of the regulatory subunit HIF-1␣ and the constitutively expressed subunit HIF-1␤. Low oxygen tension adverts enzymatic prolyl-residue hydroxylation by prolyl-4-hydroxylase, which, in normoxia, serves as a signal for polyubiquitination and proteosomal degradation, thereby preventing von-Hippel-Lindau (VHL)-dependent HIF degradation, leading to nuclear accumulation of HIF-1 (2). HIF-1 controls the expression of several cytokines that mediate the adaptive response to ischemia, including vascular endothelial growth factor and glucose metabolism. The prolyl-4-hydroxylase requires iron as a co-factor, and cobalt mimics the effect of hypoxia on HIF-1␣ activation (3). Cobalt administration to rats caused upregulation of HIF-dependent proteins, including EPO, and diminished the degree of renal injury caused by ischemia-reperfusion (I/R), suggesting the HIF/EPO pathway may play an important role in ischemic preconditioning (4). EPO is upregulated in the brain and spinal cord after hypoxic stimuli and protects neurones against ischemic or oxidative injury in vivo and in vitro (5,6). The neuroprotective effects of EPO are dependent on EPO receptormediated JAK2 phosphorylation and NF-B-dependent transcription of antiapoptotic genes, including endogenous inhibitors of apoptosis XIAP and cIAP-2 (7). In the retina, EPO upregulation is essential for hypoxic preconditioning via HIF-1␣ stabilization. The systemic administration of recombinant EPO also reduces the degree of retinal apoptosis induced by high-intensity light insult (8). EPO receptor-mediated intracellular signaling may involve nuclear translocation of the transcription factor NF-B and phosphorylation of Akt (protein kinase B) by phosph...

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Monitoring changes in gene expression in renal ischemia-reperfusion in the rat

Cited by 127 publications

References 50 publications

Abnormal expression and processing of uromodulin in Fabry disease reflects tubular cell storage alteration and is reversible by enzyme replacement therapy

Abnormal expression and processing of uromodulin in Fabry disease reflects tubular cell storage alteration and is reversible by enzyme replacement therapy

Cell-specific translational profiling in acute kidney injury

Erythropoietin Protects the Kidney against the Injury and Dysfunction Caused by Ischemia-Reperfusion

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