Impact of acute kidney injury on distant organ function: recent findings and potential therapeutic targets

Abstract Background Sepsis and septic shock are life-threatening diseases with high mortality rate in intensive care unit (ICU). Acute kidney injury (AKI) is a common complication of sepsis, and its occurrence is a poor prognostic sign to septic patients. We analyzed co-differentially expressed genes (co-DEGs) to explore relationships between septic shock and AKI and reveal potential biomarkers and therapeutic targets of septic-shock-associated AKI (SSAKI). Methods Two gene expression datasets (GSE30718 and GSE57065) were downloaded from the Gene Expression Omnibus (GEO). The GSE57065 dataset included 28 septic shock patients and 25 healthy volunteers and blood samples were collected within 0.5, 24 and 48 h after shock. Specimens of GSE30718 were collected from 26 patients with AKI and 11 control patents. AKI-DEGs and septic-shock-DEGs were identified using the two datasets. Subsequently, Gene Ontology (GO) functional analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis, and protein-protein interaction (PPI) network analysis were performed to elucidate molecular mechanisms of DEGs. We also evaluated co-DEGs and corresponding predicted miRNAs involved in septic shock and AKI. Results We identified 62 DEGs in AKI specimens and 888, 870, and 717 DEGs in septic shock blood samples within 0.5, 24 and 48 h, respectively. The hub genes of EGF and OLFM4 may be involved in AKI and QPCT, CKAP4, PRKCQ, PLAC8, PRC1, BCL9L, ATP11B, KLHL2, LDLRAP1, NDUFAF1, IFIT2, CSF1R, HGF, NRN1, GZMB, and STAT4 may be associated with septic shock. Besides, co-DEGs of VMP1, SLPI, PTX3, TIMP1, OLFM4, LCN2, and S100A9 coupled with corresponding predicted miRNAs, especially miR-29b-3p, miR-152-3p, and miR-223-3p may be regarded as promising targets for the diagnosis and treatment of SSAKI in the future. Conclusions Septic shock and AKI are related and VMP1, SLPI, PTX3, TIMP1, OLFM4, LCN2, and S100A9 genes are significantly associated with novel biomarkers involved in the occurrence and development of SSAKI.

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Acute lung injury complicating acute kidney injury: A model of endogenous αKlotho deficiency and distant organ dysfunction

Bone ◽

10.1016/j.bone.2017.03.047 ◽

2017 ◽

Vol 100 ◽

pp. 100-109 ◽

Cited By ~ 12

Author(s):

Connie C.W. Hsia ◽

Priya Ravikumar ◽

Jianfeng Ye

Keyword(s):

Acute Kidney Injury ◽

Acute Lung Injury ◽

Lung Injury ◽

Organ Dysfunction ◽

Kidney Injury ◽

Distant Organ

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Distant organ injury following acute kidney injury

AJP Renal Physiology ◽

10.1152/ajprenal.00159.2007 ◽

2007 ◽

Vol 293 (1) ◽

pp. F28-F29 ◽

Cited By ~ 25

Author(s):

Alaa S. Awad ◽

Mark D. Okusa

Keyword(s):

Acute Kidney Injury ◽

Kidney Injury ◽

Organ Injury ◽

Distant Organ

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N-Acetylcysteine Attenuates the Increasing Severity of Distant Organ Liver Dysfunction after Acute Kidney Injury in Rats Exposed to Bisphenol A

Antioxidants ◽

10.3390/antiox8100497 ◽

2019 ◽

Vol 8 (10) ◽

pp. 497 ◽

Cited By ~ 3

Author(s):

Wachirasek Peerapanyasut ◽

Anongporn Kobroob ◽

Siripong Palee ◽

Nipon Chattipakorn ◽

Orawan Wongmekiat

Keyword(s):

Oxidative Stress ◽

Acute Kidney Injury ◽

Liver Injury ◽

Bisphenol A ◽

Kidney Injury ◽

Causative Factor ◽

Mitochondrial Homeostasis ◽

Systemic Oxidative Stress ◽

Mitochondrial Functions ◽

Distant Organ

Distant organ liver damage after acute kidney injury (AKI) remains a serious clinical setting with high mortality. This undesirable outcome may be due to some hidden factors that can intensify the consequences of AKI. Exposure to bisphenol A (BPA), a universal chemical used in plastics industry, is currently unavoidable and can be harmful to the liver. This study explored whether BPA exposure could be a causative factor that increase severity of remote liver injury after AKI and examined the preventive benefit by N-acetylcysteine (NAC) in this complex condition. Male Wistar rats were given vehicle, BPA, or BPA + NAC for 5 weeks then underwent 45 min renal ischemia followed by 24 h reperfusion (RIR), a group of vehicle-sham-control was also included. RIR not only induced AKI but produced liver injury, triggered systemic oxidative stress as well as inflammation, which increasing severity upon exposure to BPA. Given NAC to BPA-exposed rats diminished the added-on effects of BPA on liver functional impairment, oxidative stress, inflammation, and apoptosis caused by AKI. NAC also mitigated the abnormalities in mitochondrial functions, dynamics, mitophagy, and ultrastructure of the liver by improving the mitochondrial homeostasis regulatory signaling AMPK-PGC-1α-SIRT3. The study demonstrates that NAC is an effective adjunct for preserving mitochondrial homeostasis and reducing remote effects of AKI in environments where BPA exposure is vulnerable.

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Abstract 12622: Pro-inflammatory Urinary CXCL10 and VCAM Are Elevated After Infant Cardiac Surgery-associated Acute Kidney Injury (AKI)

Circulation ◽

10.1161/circ.142.suppl_3.12622 ◽

2020 ◽

Vol 142 (Suppl_3) ◽

Author(s):

Daniella Levy- Erez ◽

Lokesh Shah ◽

Kathryn D Howarth ◽

Sherin Meloni ◽

Benjamin Laskin ◽

...

Keyword(s):

Acute Kidney Injury ◽

Cardiac Surgery ◽

Therapeutic Targets ◽

Kidney Injury ◽

Urine Samples ◽

Inflammatory Biomarkers ◽

Rank Test ◽

Immune Biomarkers ◽

The Relationship ◽

Complex Surgery

Introduction: Acute kidney injury (AKI) occurs frequently after infant cardiac surgery and is associated with mortality. AKI mechanisms are unknown, limiting therapeutic targets. Emerging data implicates unregulated immune activation and AKI development. Hypothesis: Urinary immune biomarkers will be elevated in the urine of infants developing AKI. Methods: One hundred and twenty six infants were enrolled (median age 87 days, 74% male). Urine samples were collected pre-bypass and 6, 24, 48, and 72 hours after surgery. Urine samples underwent multiplex Luminex assays to detect six immune biomarkers: VCAM, CXCL10, MCP, IL-18, TWEAK, and C5-C9. Greater than 150% increase in serum creatinine defined AKI. The Kruskal-Wallis rank test determined the relationship between AKI and biomarker levels. Results: Thirty-five infants (27%) developed AKI. AKI subjects were younger (median 6 days (4-98) vs no AKI 107 days (7-164), p<0.01). The AKI group had more complex surgery (STAT 4-5) (60% AKI vs 19% no AKI, p<0.01). Bypass time was longer among the AKI group ((81 min vs 69 min (p<0.01)).AKI infants had higher urinary CXCL10 levels at 24 hours (14.3 pg/ml vs 5.3 pg/ml p=0.04), 48 hours (3.4 pg/ml vs 0.75 pg/ml p=0.01), and 72 hours (1.15 pg/ml vs 0.22 pg/ml p=0.05) (Figure 1). Six-hour VCAM levels were higher among AKI infants (Median 491 pg/ml vs 0 pg/ml p=0.04). Other biomarkers showed no significant differences between groups. (Table1). Conclusions: Urinary CXCL10 and VCAM are promising pro-inflammatory biomarkers for early AKI detection and may indicate eventual AKI therapeutic targets.

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Identification of novel therapeutic targets for contrast induced acute kidney injury (CI-AKI): alpha blockers as a therapeutic strategy for CI-AKI

Translational Research ◽

10.1016/j.trsl.2021.03.005 ◽

2021 ◽

Author(s):

Sreenivasulu Kilari ◽

Amit Sharma ◽

Chenglei Zhao ◽

Avishek Singh ◽

Chuanqi Cai ◽

...

Keyword(s):

Acute Kidney Injury ◽

Therapeutic Strategy ◽

Therapeutic Targets ◽

Kidney Injury ◽

Alpha Blockers ◽

Novel Therapeutic

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Netrin-1 regulates colon-kidney cross talk through suppression of IL-6 function in a mouse model of DSS-colitis

AJP Renal Physiology ◽

10.1152/ajprenal.00702.2012 ◽

2013 ◽

Vol 304 (9) ◽

pp. F1187-F1197 ◽

Cited By ~ 15

Author(s):

Punithavathi Ranganathan ◽

Calpurnia Jayakumar ◽

Manicassamy Santhakumar ◽

Ganesan Ramesh

Keyword(s):

Acute Kidney Injury ◽

Transgenic Mice ◽

Cross Talk ◽

Inflammatory Mediators ◽

Kidney Injury ◽

Organ Injury ◽

Protective Effects ◽

Chemokine Production ◽

Dss Colitis ◽

Distant Organ

Organ cross talk is increasingly appreciated in human disease, and inflammatory mediators are shown to mediate distant organ injury in many disease models. Colitis and intestinal injury are known to be mediated by infiltrating immune cells and their secreted cytokines. However, its effect on other organs, such as the kidney, has never been studied. In the current study, we examined the effect of dextran sulfate sodium (DSS)-colitis on kidney injury and inflammation. In addition, we hypothesized that netrin-1 could modulate colon-kidney cross talk through regulation of inflammation and apoptosis. Consistent with our hypothesis, DSS-colitis induced acute kidney injury in mice. Epithelial-specific overexpression of netrin-1 suppressed both colitis and colitis-induced acute kidney injury, which was associated with reduced weight loss, neutrophil infiltration into colon mucosa, intestinal permeability, epithelial cell apoptosis, and cytokine and chemokine production in netrin-1 transgenic mice colon and kidney. To determine whether netrin-1-protective effects were mediated through suppression of IL-6, IL-6 knockout mice were treated with DSS and acute kidney injury was determined. IL-6 knockout was resistant to colitis and acute kidney injury. Moreover, administration of IL-6 to netrin-1 transgenic mice did not affect the netrin-1-protective effects on the colon and kidney, suggesting that netrin-1 may reduce both IL-6 production and its activity. The present study identifies previously unrecognized cross talk between the colon and kidney, and netrin-1 may limit distant organ injury by suppressing inflammatory mediators and apoptosis.

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