Dataset Information

CXCL12 and MYC control energy metabolism to support adaptive responses after kidney injury

ABSTRACT: Kidney injury is a common complication of severe disease. Here, we report that injuries of the zebrafish embryonal kidney are rapidly repaired by a migratory response in 2-, but not in 1-day-old embryos. Gene expression profiles between these two developmental stages identify cxcl12a and myca as candidates involved in the repair process. Zebrafish embryos with cxcl12a, cxcr4b, or myca deficiency display repair abnormalities, confirming their role in response to injury. In mice with a kidney-specific knockout, Cxcl12 and Myc gene deletions suppress mitochondrial metabolism and glycolysis, and delay the recovery after ischemia/reperfusion injury. Probing these observations in zebrafish reveal that inhibition of glycolysis slows fast migrating cells and delays the repair after injury, but does not affect the slow cell movements during kidney development. Our findings demonstrate that Cxcl12 and Myc facilitate glycolysis to promote fast migratory responses during development and repair, and potentially also during tumor invasion and metastasis.

OTHER RELATED OMICS DATASETS IN: PRJNA236469

INSTRUMENT(S): Nuclear Magnetic Resonance (NMR)

SUBMITTER: Justine Leenders

PROVIDER: MTBLS723 | MetaboLights | 2018-10-11

REPOSITORIES: MetaboLights

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			Action	DRS
	MTBLS723	Other
	FILES	Other
	a_MTBLS723_cxl12_-_myc_metabolite_profiling_NMR_spectroscopy.txt	Txt
	i_Investigation.txt	Txt
	m_MTBLS723_cxl12_-_myc_metabolite_profiling_NMR_spectroscopy_v2_maf.tsv	Tabular

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CXCL12 and MYC control energy metabolism to support adaptive responses after kidney injury.

Yakulov Toma A TA Todkar Abhijeet P AP Slanchev Krasimir K Wiegel Johannes J Bona Alexandra A Groß Martin M Scholz Alexander A Hess Isabell I Wurditsch Anne A Grahammer Florian F Huber Tobias B TB Lecaudey Virginie V Bork Tillmann T Hochrein Jochen J Boerries Melanie M Leenders Justine J de Tullio Pascal P Jouret François F Kramer-Zucker Albrecht A Walz Gerd G

Nature communications 20180910 1

Kidney injury is a common complication of severe disease. Here, we report that injuries of the zebrafish embryonal kidney are rapidly repaired by a migratory response in 2-, but not in 1-day-old embryos. Gene expression profiles between these two developmental stages identify cxcl12a and myca as candidates involved in the repair process. Zebrafish embryos with cxcl12a, cxcr4b, or myca deficiency display repair abnormalities, confirming their role in response to injury. In mice with a kidney-spec ...[more]

PMID: 30202007

Similar Datasets

Project description:Injuries of the zebrafish kidney are rapidly repaired by a migratory response in two to three day-old embryos. While this migratory repair process re-establishes the integrity of the pronephric tubules independently of proliferation, fluid flow, intact cilia, or Wnt signaling, pronephros injuries before 36 hours post fertilization were repaired by a purse string-like mechanism that irreversibly occluded the pronephric tubules. Comparing the gene expression profiles between these two developmental stages and focusing on up-regulated zebrafish pronephros genes, we identified cxcl12a and myca as potential candidates orchestrating the migratory repair process. Zebrafish lines with either cxcl12a or cxcr4b mutations displayed striking repair abnormalities, confirming the requirement for cxc12a/cxcr4b signaling to override the ongoing collective cell migration and repair the pronephros injury. However, in contrast to the collective cell migration of the posterior lateral line primordium, cxc12a/cxcr4b signaling was dispensable for normal pronephros development. Zebrafish myca, the pronephros-specific homologue of human MYC, was also increased in cells participating in the repair response. The defective repair response caused by knockdown of myca resembled the abnormalities observed in cxcx12a/cxcr4b-deficient zebrafish, and was partially rescued by cxcr4b mRNA, suggesting that myca acts in part through up-regulating cxcr4b expression during the migration-based repair process. Kidney-specific knockout of Cxcl12 and Myc suppressed mitochondrial functions, reduced retinoic acid receptor signaling, and delayed the recovery after ischemic/reperfusion injury in mice. Tretinoin, known to stimulate Cxcr4 expression and mitochondrial metabolism, accelerated renal recovery. Thus, the zebrafish pronephros injury mode provides a systematic approach to identify molecules involved in the immediate repair response after kidney injury, and to design strategies to ameliorate this severe complication of human disease.

Project description:Microarray analysis of human kidneys with acute kidney injury (AKI) has been limited because such kidneys are seldom biopsied. However, all kidney transplants experience AKI, and early kidney transplants without rejection are an excellent model for human AKI: they are screened to exclude chronic kidney disease, frequently biopsied, and have extensive follow-up. We used histopathology and microarrays to compare indication biopsies from 28 transplants with AKI to 11 pristine protocol biopsies of stable transplants. Kidneys with AKI showed increased expression of 394 injury-repair response associated transcripts, including many known epithelial injury molecules (e.g. ITGB6, LCN2), tissue remodeling molecules (e.g. VCAN), and inflammation molecules (S100A8, ITGB3). Many other genes also predict the phenotype, depending on statistical filtering rules, including AKI biomarkers as HAVCR1 and IL18. Most mouse orthologs of the top injury-repair transcripts were increased in published mouse AKI models. Pathway analysis of the injury-repair transcripts revealed similarities to cancer, development, and cell movement. The injury-repair transcript score AKI kidneys correlated with reduced function, future recovery, brain death, and need for dialysis, but not future graft loss. In contrast, histologic features of "acute tubular injury" did not correlate with function or with the molecular changes. Thus the injury-repair associated transcripts represent a massive coordinate injury-repair response of kidney parenchyma to AKI, similar to mouse AKI models, and provide an objective measure for assessing the severity of AKI in kidney biopsies and validation for the use of many AKI biomarkers. AKI biopsies sample names and CEL files are from GSE21374. All consenting renal transplant patients undergoing biopsies for cause as standard of care between 09/2004 and 10/2007 at the university of Alberta or between 11/2006 and 02/2007 at the University of Illinois were included in the analysis. In addition to the cores required for standard histopathology, we collected one core for gene expression studies. the relationship between gene expression in the biopsy and subsequent graft loss was analyzed. This dataset is part of the TransQST collection.

Project description:Fibroblasts are present in every organ. While the role fibroblasts in chronic diseases such as fibrosis or tumor expression has been extensively explored, little is known about their physiological role. The kidney possesses a unique capacity to recover from even severe acute injury. We study molecular mechanisms of this intrinsic repair capacity in the mouse model of ischemia-reperfusion (IR). In this model, the renal artery and vein are clamped for 45 min, leading to acute kidney injury. The kidney spontaneously recovers from such IR injury within 14 days. IR kidney injury is associated with a transient accumulation of fibroblasts in the diseased tissue. We hypothesized that fibroblasts aid the repair of acute IR injury in the kidney. To elucidate how FSP1+ fibroblasts may contribute to the repair of kidney injury, we undertook a global unbiased approach to compare gene expression profiles of fibroblasts isolated from kidneys post-IRI and from control kidneys by FACS sorting. To investigate the role fibroblasts may play in the repair of kidney inhury, we performed ischemia reperfusion injury surgery on transgenic mice in which the FSP-1 promoter drives EGFP expression. Kidney injury peaks at day 3 post-IRI, followed by spontaneous regeration that restores nearly perfect kidney architecture and health by day 10. Fibroblasts are thought to possibly play a role in this process, as they are normally rare in the healthy kidney, acute kidney injury is associated with a transient accumulation of interstitial fibroblasts, but whether they may help repair the acute kidney injury or in fact could contribute to the damage is not known. To compare the gene expression profiles of normal fibroblasts and those from post-ischemic kidneys, we sacrificed control FSP1-GFP mice and the FSP1-GFP mice three days post-IRI. We generated single-cell suspensions from both the post-IRI and control kidneys, and then isolated FSP1-GFP+ cells by FACS sorting that, when cultured on plastic, displayed typical fibroblast morphology. Total RNA was immediately extracted from the sorted cells and amplified to produce enough for a array. We biotinylated five of the samples from post-ischemic kidneys and three of the control (non-ischemic) kidneys and used Affymetrix 3' Arrays to examine differences in gene expression profiles between the two groups that may she some light on what role, if any, fibroblasts play in the spontaneous healing of the kidney after acute kidney injury. We performed ischemia reperfusion surgery in FSP1-GFP mice, and at day 3, we sacrificed the mice, isolated FSP1-GFP positive cells from both IR and normal control kidneys by FACS sorting, extracted total RNA from the isolated FSP1-GFP cells and used Affymetrix Mouse Expression Array 430 2.0 microarrays to perform gene expression profiling of the samples. All told, we performed the FACS Sorting, RNA extration, and hybridization with 5 ischemic kidneys and 3 normal kidneys. Fibroblasts, acute kidney injury, repair, comparative gene expression profiling, microarrays, FACS sorting, role in healing