Gene expression in early ischemic renal injury: clues towards pathogenesis, biomarker discovery, and novel therapeutics

Devarajan, Prasad; Mishra, Jaya; Supavekin, Suroj; Patterson, Larry T.; Potter, S Steven

doi:10.1016/j.ymgme.2003.09.012

Cited by 211 publications

(153 citation statements)

References 80 publications

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“…Such postnatal repair has been proposed to involve the re-expression of genes previously critical to the development of the normal kidney. Indeed, the re-expression of developmental genes in response to renal damage has been reported in a number of human diseases and animal models, including ischaemia-reperfusion injury and diabetes [10,11]. However, the re-expression of Six2 in response to tubular injury, which might signal the reactivation of the embryonic nephron induction pathway, is not observed [12].…”

Section: Renal Repair Recapitulating Development: Yes or No?mentioning

confidence: 99%

Stem cell options for kidney disease

Hopkins

Rae

et al. 2008

The Journal of Pathology

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Chronic kidney disease (CKD) is increasing at the rate of 6-8% per annum in the US alone. At present, dialysis and transplantation remain the only treatment options. However, there is hope that stem cells and regenerative medicine may provide additional regenerative options for kidney disease. Such new treatments might involve induction of repair using endogenous or exogenous stem cells or the reprogramming of the organ to reinitiate development. This review addresses the current state of understanding with respect to the ability of non-renal stem cell sources to influence renal repair, the existence of endogenous renal stem cells and the biology of normal renal repair in response to damage. Understanding repair options via an understanding of renal developmentThe prevalence and incidence of chronic kidney disease (CKD) is increasing at 6-8% per annum in the USA alone, largely as a result of increased prevalence of diabetes and obesity [1]. To understand what might be possible with respect to cellular therapies or regenerative medicine for the kidney, one first needs to consider what is understood about normal renal development and response to injury. The kidney has been classically regarded as an organ with minimal cellular turnover and no capacity for regeneration. The subsequent identification of stem cells in a number of such organs, including the brain, has challenged this view. However, the dogma remains that the kidney reaches a maximal complement of nephrons and then loses these over time [2]. This dogma is drawn from our understanding of the development of this organ. The progenitor population during developmentThe kidney is mesodermal in origin and develops from two populations derived from intermediate mesoderm, the ureteric bud (UB) and the metanephric mesenchyme (MM). While an even broader potential had been proposed [3], genetic and lineage analyses have confirmed that the MM gives rise to all portions of the nephron other than the collecting ducts and also gives rise to elements of the renal interstitium [4][5][6]. The UB gives rise to the ureter and collecting ducts only. The MM is apparently not homogeneous but forms condensed mesenchyme around the tips of the branching UB. This cap mesenchyme (CM) contains self-renewing progenitors capable of generating all cells of the nephron other than the collecting ducts via an initial mesenchyme-epithelial transition (MET) event throughout the prenatal developmental period [6]. The continued expression of the transcription factor Six2 in CM is required for maintenance of this stem cell population during kidney development [5]. As the UB branches and extends through the MM, individual MET events occur at the underside of each tip to form a new nephron [2]. This nephron endowment therefore proceeds from the centre of the kidney out to the periphery, with the CM stem cell field remaining on the outer edge of the expanding organ. Endowment of new nephrons is restricted to prenatal development in humans, while in rodents it persists only until the imm...

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Section: Renal Repair Recapitulating Development: Yes or No?mentioning

confidence: 99%

Stem cell options for kidney disease

Hopkins

Rae

et al. 2008

The Journal of Pathology

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“…[14] Briefly, it is a sandwich monoclonal ELISA procedure determining NGAL and IL-18 in human urine. Microtiter platelets coated with monoclonal antibodies against human NGAL or IL-18 were coated with samples (urine) or standards (NGAL or IL-18 concentrations ranging from 1 to 1,000 μg/L), which was read at 450 nm with a microplate reader (BIO-TEK, ELX-808, Winooski, Vermont, USA).…”

Section: Test Of Ngal and Il-18 By Elisamentioning

confidence: 99%

“…(Note that the study on AKI in cardiac surgery children has already been mentioned this hypothesis. [21] ) Recently, the studies of early biomarkers for AKI hypothesized cohort candidates, such as kidney injury molecule 1, [14,24] kidney-specific adhesion molecule, sodium-hydrogen exchanger isoform 3, interleukin 6, interleukin 8, cystatin C, and so on. Some got a conflicting and unsatisfactory result, while most showed optimistic results.…”

Section: Urine Ngal and Il-18 Predict Aki After Cardiac Surgerymentioning

confidence: 99%

Urine Neutrophil Gelatinase-Associated Lipocalin and Interleukin-18 Predict Acute Kidney Injury after Cardiac Surgery

et al. 2008

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Background. About 30-50% patients develop acute kidney injury (AKI) after cardiac surgery, which is still diagnosed by serum creatinine on clinic. However, the increase of serum creatinine is insensitive and delayed. The aim of this study is to test the hypothesis that neutrophil gelatinase-associated lipocalin (NGAL) and interleukin-18 (IL-18) are early biomarkers for AKI in patients after cardiac surgery. Methods. Thirty-three cases undergoing cardiac surgery were classified into an AKI group and non-AKI group, according to the AKI definition (> 26.5 μmol/L increase of serum creatinine, more than or equal to 50% increase of serum creatinine within 48 h, or a reduction in urine output < 0.5 mL/Kg per hour for more than six hours). The concentrations of serum NGAL, urine NGAL, and urine IL-18 at different time-points were measured. Results. Nine cases (27.27%) developed postoperative AKI, but diagnosis with serum creatinine was 12-48 h postoperation. The concentrations of serum NGAL were not significantly increased postoperation. The concentrations of urine NGAL and IL-18 were significantly increased in the AKI group, which reached the peak at 2-4 h postoperation, and a more significant difference could be seen after correction for urine creatinine. The concentrations of urine NGAL and IL-18 2 h postoperation, either corrected for urine creatinine or not, showed good sensitivity and specificity. Increased levels of urine NGAL and IL-18 2 h postoperation were significantly correlated with increased level of serum creatinine 12 h postoperation. Logistic regression analysis showed that urine NGAL corrected for urine creatinine 2 h postoperation and urine IL-18 2 h postoperation emerged as powerful independent predictors of AKI after cardiac surgery. Conclusions. The concentrations of urine NGAL and IL-18 could be useful biomarkers for AKI in patients after cardiac surgery, especially after correction for urine creatinine.

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“…The most common strategy (Figure 3a) is to subtract normal from diseased tissue, either using representative difference analysis (32) or by microarrays (33). One then hopes that protein will follow RNA levels, which is not always the case (34 -37), and that the protein will be detectable in serum or urine.…”

Section: Step 4: Devise a Strategy For The Discovery Processmentioning

confidence: 99%

Discovery of Protein Biomarkers for Renal Diseases

Hewitt¹,

Dear²,

Star³

2004

Journal of the American Society of Nephrology

269

150

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Abstract. Animal models and human studies have been useful in dissecting the molecular mechanisms of renal disease and finding new disease targets; however, translation of these findings to new clinical therapeutics remains challenging. Difficulties with detecting early disease, measuring drug effectiveness, and the daunting cost of clinical trials hampers the development of new therapeutics for renal diseases. Many existing laboratory tests were discovered because of inspired recognition that a particular protein might prove useful in clinical practice. New unbiased genomic and proteomic techniques identify many constituents present in biologic samples and thus may greatly accelerate biomarker research. This review focuses on the steps needed to develop new biomarkers that are useful in laboratory and clinical investigations, with particular focus on new proteomic screening technologies. New biomarkers will speed the laboratory and clinical development of new treatments for renal diseases through mechanistic insights, diagnoses that are more refined, early detection, and enhanced proof of concept testing.

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Gene expression in early ischemic renal injury: clues towards pathogenesis, biomarker discovery, and novel therapeutics

Cited by 211 publications

References 80 publications

Stem cell options for kidney disease

Stem cell options for kidney disease

Urine Neutrophil Gelatinase-Associated Lipocalin and Interleukin-18 Predict Acute Kidney Injury after Cardiac Surgery

Discovery of Protein Biomarkers for Renal Diseases

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