Dataset Information

Reperfusion Activates AP-1 and Heat Shock Response in Donor Kidney Parenchyma after Warm Ischemia.

ABSTRACT: Utilization of kidneys from extended criteria donors leads to an increase in average warm ischemia time (WIT), which is associated with larger degrees of ischemia-reperfusion injury (IRI). Kidney resuscitation by extracorporeal perfusion in situ allows up to 60 minutes of asystole after the circulatory death. Molecular studies of kidney grafts from human donors with critically expanded WIT are warranted. Transcriptomes of two human kidneys from two different donors were profiled after 35-45 minutes of WIT and after 120 minutes of normothermic perfusion and compared. Baseline gene expression patterns in ischemic grafts display substantial intrinsic differences. IRI does not lead to substantial change in overall transcription landscape but activates a highly connected protein network with hubs centered on Jun/Fos/ATF transcription factors and HSP1A/HSPA5 heat shock proteins. This response is regulated by positive feedback. IRI networks are enriched in soluble proteins and biofluids assayable substances, thus, indicating feasibility of the longitudinal, minimally invasive assessment in vivo. Mapping of IRI related molecules in ischemic and reperfused kidneys provides a rationale for possible organ conditioning during machine assisted ex vivo normothermic perfusion. A study of natural diversity of the transcriptional landscapes in presumably normal, transplantation-suitable human organs is warranted.

SUBMITTER: Reznik A

PROVIDER: S-EPMC6116402 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Reperfusion Activates AP-1 and Heat Shock Response in Donor Kidney Parenchyma after Warm Ischemia.

Reznik Alexandr A Plotnikova Olga O Skvortsov Andrey A Skoblov Mikhail M Reznik Oleg O Baranova Ancha A

BioMed research international 20180816

Utilization of kidneys from extended criteria donors leads to an increase in average warm ischemia time (WIT), which is associated with larger degrees of ischemia-reperfusion injury (IRI). Kidney resuscitation by extracorporeal perfusion in situ allows up to 60 minutes of asystole after the circulatory death. Molecular studies of kidney grafts from human donors with critically expanded WIT are warranted. Transcriptomes of two human kidneys from two different donors were profiled after 35-45 minu ...[more]

PMID: 30186861

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Project description:Ischemic acute kidney injury (AKI) has always been a hot and difficult research topic in the field of renal diseases. This study aims to illustrate the safe warm ischemia time of kidney and the molecular network characteristics and pathological features of mild to severe ischemia reperfusion kidney injury. We established varying degrees of renal injury due to different ischemia time (0 min, 16 min, 18 min, 20 min, 22 min, 24 min, 26 min, 28 min, and 30 min) on unilateral (left kidney) ischemia-reperfusion injury and contralateral (right kidney) resection (uIRIx) mouse model. Mice were sacrificed 24 h after uIRIx, blood samples were harvested to detect serum creatinine (Scr), and kidney tissue samples were harvested to perform Periodic Acid-Schiff (PAS) staining and RNA-Seq. Differentially expressed genes (DEGs) were identificated, time-dependent gene expression patterns and functional enrichment analysis were further performed. Finally, qPCR was performed to validated RNA-Seq results. Our results indicated that there was no absolute safe renal warm ischemia time, and every minute of ischemia increases kidney damage. Warm ischemia 26min or above in mice makes severe kidney injury, renal pathology and SCr were both significantly changed. Warm ischemia between 18 and 26 min makes mild kidney injury, with changes in pathology and renal molecular expression, while SCr did not change. No obvious pathological changes but significant differences in molecular expression were found less than 16min warm ischemia. There are two key time intervals in the process of renal ischemia injury, 0 min-16 min (short-term) and 26 min-28 min (long-term). Gene expression of immune-related pathways were most significantly down-regulated in short-term ischemia, while metabolism-related pathways were the mainly enriched pathway in long-term ischemia. Taken together, this study provides novel insights into safe renal artery occlusion time in partial nephrectomy, and is of great value for elucidating molecular network characteristics and pathological features of mild to severe ischemia reperfusion kidney injury, and key genes related to metabolism and immune found in this study also provide potential diagnostic and therapeutic biomarkers for AKI.

Project description:BackgroundHeat shock protein 70 (Hsp70) has been shown to exert cardioprotection. Intracellular calcium ([Ca2+]i) overload induced by p38 mitogen-activated protein kinase (p38 MAPK) activation contributes to cardiac ischemia/reperfusion (I/R) injury. However, whether Hsp70 interacts with p38 MAPK signaling is unclear. Therefore, this study investigated the regulation of p38 MAPK by Hsp70 in I/R-induced cardiac injury.MethodsNeonatal rat cardiomyocytes were subjected to oxygen-glucose deprivation for 6 h followed by 2 h reoxygenation (OGD/R), and rats underwent left anterior artery ligation for 30 min followed by 30 min of reperfusion. The p38 MAPK inhibitor (SB203580), Hsp70 inhibitor (Quercetin), and Hsp70 short hairpin RNA (shRNA) were used prior to OGD/R or I/R. Cell viability, lactate dehydrogenase (LDH) release, serum cardiac troponin I (cTnI), [Ca2+]i levels, cell apoptosis, myocardial infarct size, mRNA level of IL-1β and IL-6, and protein expression of Hsp70, phosphorylated p38 MAPK (p-p38 MAPK), sarcoplasmic/endoplasmic reticulum Ca2+-ATPase2 (SERCA2), phosphorylated signal transducer and activator of transcription3 (p-STAT3), and cleaved caspase3 were assessed.ResultsPretreatment with a p38 MAPK inhibitor, SB203580, significantly attenuated OGD/R-induced cell injury or I/R-induced myocardial injury, as evidenced by improved cell viability and lower LDH release, resulted in lower serum cTnI and myocardial infarct size, alleviation of [Ca2+]i overload and cell apoptosis, inhibition of IL-1β and IL-6, and modulation of protein expressions of p-p38 MAPK, SERCA2, p-STAT3, and cleaved-caspase3. Knockdown of Hsp70 by shRNA exacerbated OGD/R-induced cell injury, which was effectively abolished by SB203580. Moreover, inhibition of Hsp70 by quercetin enhanced I/R-induced myocardial injury, while SB203580 pretreatment reversed the harmful effects caused by quercetin.ConclusionsInhibition of Hsp70 aggravates [Ca2+]i overload, inflammation, and apoptosis through regulating p38 MAPK signaling during cardiac I/R injury, which may help provide novel insight into cardioprotective strategies.

Dataset Information

Reperfusion Activates AP-1 and Heat Shock Response in Donor Kidney Parenchyma after Warm Ischemia.

Publications

Reperfusion Activates AP-1 and Heat Shock Response in Donor Kidney Parenchyma after Warm Ischemia.

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