SIRT3 mediates Mitofusin 2 ubiquitination and degradation to suppress ischemia reperfusion-induced acute kidney injury

Abstract Background and Aims Studies have shown that serum response factor (SRF) is increased in chronic kidney injury, such as diabetic nephropathy, hyperuricemic nephropathy and renal cell carcinoma. The objective is to explore the early diagnostic value of SRF in acute kidney injury (AKI). Method AKI-related microarray data were analyzed, and the expression and location of SRF were investigated in the early phase of AKI. Results Bioinformatics results demonstrated that SRF was dramatically elevated 2-4 h after ischemia/reperfusion (I/R) in mouse renal tissue. In I/R rats, SRF was mostly expressed and located in renal tubular epithelial cells (TECs). SRF started to increase at 1 h, peaked at 3-9 h and started to decrease at 12 h after I/R. The areas under the ROC curve of renal SRF mRNA, renal SRF protein, urinary SRF, serum SRF and serum creatinine (Scr) were 87.9%, 83.0%, 81.3%, 78.8%, 68.8%, respectively. Conclusion SRF is remarkably upregulated in early (before 24 h) AKI and can replace Scr as a potential new early diagnostic biomarker of AKI.

Download Full-text

Reducing Inflammatory Cytokine Production from Renal Collecting Duct Cells by Inhibiting GATA2 Ameliorates Acute Kidney Injury

Molecular and Cellular Biology ◽

10.1128/mcb.00211-17 ◽

2017 ◽

Vol 37 (22) ◽

Cited By ~ 9

Author(s):

Lei Yu ◽

Takashi Moriguchi ◽

Hiroshi Kaneko ◽

Makiko Hayashi ◽

Atsushi Hasegawa ◽

...

Keyword(s):

Acute Kidney Injury ◽

Inflammatory Cytokines ◽

Inflammatory Cytokine ◽

Cytokine Production ◽

Ischemia Reperfusion Injury ◽

Collecting Duct ◽

Ischemia Reperfusion ◽

Kidney Injury ◽

Cytokine Gene Expression ◽

Renal Tubular Cell

ABSTRACT Acute kidney injury (AKI) is a leading cause of chronic kidney disease. Proximal tubules are considered to be the primary origin of pathogenic inflammatory cytokines in AKI. However, it remains unclear whether other cell types, including collecting duct (CD) cells, participate in inflammatory processes. The transcription factor GATA2 is specifically expressed in CD cells and maintains their cellular identity. To explore the pathophysiological function of GATA2 in AKI, we generated renal tubular cell-specific Gata2 deletion (G2CKO) mice and examined their susceptibility to ischemia reperfusion injury (IRI). Notably, G2CKO mice exhibited less severe kidney damage, with reduced granulomacrophagic infiltration upon IRI. Transcriptome analysis revealed that a series of inflammatory cytokine genes were downregulated in GATA2-deficient CD cells, suggesting that GATA2 induces inflammatory cytokine expression in diseased kidney CD cells. Through high-throughput chemical library screening, we identified a potent GATA inhibitor. The chemical reduces cytokine production in CD cells and protects the mouse kidney from IRI. These results revealed a novel pathological mechanism of renal IRI, namely, that CD cells produce inflammatory cytokines and promote IRI progression. In injured kidney CD cells, GATA2 exerts a proinflammatory function by upregulating inflammatory cytokine gene expression. GATA2 can therefore be considered a therapeutic target for AKI.

Download Full-text

Adipose tissue derived mesenchymal stem cell transplantation in the treatment of ischemia/reperfusion induced acute kidney injury in rats. Application route and therapeutic window

Acta Cirurgica Brasileira ◽

10.1590/s0102-865020180110000008 ◽

2018 ◽

Vol 33 (11) ◽

pp. 1016-1026 ◽

Cited By ~ 4

Author(s):

Betânia Souza Monteiro ◽

Bianka Souza dos Santos ◽

Bruna Lopes de Almeida ◽

Emy Hiura ◽

Wagner Alexey Back Fiorio ◽

...

Keyword(s):

Acute Kidney Injury ◽

Adipose Tissue ◽

Stem Cell ◽

Mesenchymal Stem Cell ◽

Stem Cell Transplantation ◽

Cell Transplantation ◽

Ischemia Reperfusion ◽

Kidney Injury ◽

Therapeutic Window ◽

Mesenchymal Stem Cell Transplantation

Download Full-text

THE STUDY OF RENOPROTECTIVE PROPERTIES OF ERYTROPOETIN DERIVATIVES ON THE KIDNEY ISCHEMIA-REPERFUSION MODEL

Kuban Scientific Medical Bulletin ◽

10.25207/1608-6228-2018-25-6-73-77 ◽

2018 ◽

Vol 25 (6) ◽

pp. 73-77 ◽

Cited By ~ 1

Author(s):

V. V. Elagin ◽

D. A. Kostina ◽

O. I. Bratchikov ◽

M. V. Pokrovsky ◽

T. G. Pokrovskaya

Keyword(s):

Acute Kidney Injury ◽

Glomerular Filtration Rate ◽

Glomerular Filtration ◽

Sodium Excretion ◽

Filtration Rate ◽

Ischemia Reperfusion ◽

Kidney Injury ◽

Fractional Sodium Excretion ◽

Male Wistar Rats ◽

Microcirculatory Disorders

Aim.The research was designed to study the renoprotective properties of erythropoietin derivatives on the kidney ischemiareperfusion experimental model.Materials and methods.The renoprotective properties of asialo erythropoietin (0.4 μg/kg and 2.4 μg/kg 30 minutes before the induction of ischemia) and carbamylated darbepoetin (50 μg/kg 24 hours before the ischemic stimulus) were studied in comparison with erythropoietin and darbepoetin in a series of experiments on male Wistar rats on a 40-minute bilateral model of renal ischemia-reperfusion. The renoprotective properties were evaluated by the results of biochemical markers of acute kidney injury, the dynamics of glomerular filtration rate and fractional sodium excretion, as well as the severity of microcirculatory disorders.Results.It was found that the prophylactic use of asialo erythropoietin (dose-dependent) and carbamylated darbepoetin leads to a decrease in the serum concentration of markers of acute renal damage, an increase in the glomerular filtration rate, a decrease in fractional sodium excretion, and a decrease in microcirculatory disorders.Conclusion.Asialo erythropoietin and carbamylated darbepoetin have the pronounced renoprotective properties and are the promising agents for the prevention and treatment of acute kidney injury.

Download Full-text

Soluble receptor for advanced glycation end products protects from ischemia- and reperfusion-induced acute kidney injury

Biology Open ◽

10.1242/bio.058852 ◽

2021 ◽

Author(s):

Taro Miyagawa ◽

Yasunori Iwata ◽

Megumi Oshima ◽

Hisayuki Ogura ◽

Koichi Sato ◽

...

Keyword(s):

Acute Kidney Injury ◽

Advanced Glycation End Products ◽

Ischemia Reperfusion ◽

Kidney Injury ◽

Tubular Damage ◽

Advanced Glycation ◽

Renal Tubular Damage ◽

Glycation End Products ◽

End Products ◽

Renal Tubular

The full-length receptor for advanced glycation end products (RAGE) is a multiligand pattern recognition receptor. High-mobility group box 1 (HMGB1) is a RAGE ligand of damage-associated molecular patterns that elicits inflammatory reactions. The shedded isoform of RAGE and endogenous secretory RAGE (esRAGE), a splice variant, are soluble isoforms (sRAGE) that act as organ-protective decoys. However, the pathophysiologic roles of RAGE/sRAGE in acute kidney injury (AKI) remain unclear. We found that AKI was more severe, with enhanced renal tubular damage, macrophage infiltration, and fibrosis, in mice lacking both RAGE and sRAGE than in wild-type control mice. Using murine tubular epithelial cells (TECs), we demonstrated that hypoxia upregulated messenger RNA (mRNA) expression of HMGB1 and tumor necrosis factor α (TNF-α), whereas RAGE and esRAGE expressions were paradoxically decreased. Moreover, the addition of recombinant sRAGE canceled hypoxia-induced inflammation and promoted cell viability in cultured TECs. sRAGE administration prevented renal tubular damage in models of ischemia/reperfusion-induced AKI and of anti-glomerular basement membrane (anti-GBM) glomerulonephritis. These results suggest that sRAGE is a novel therapeutic option for AKI.

Download Full-text

Abstract 655: Ischemia-induced Epoxyeicosatrienoic Acid Release Protects Female Rats From Acute Kidney Injury

Hypertension ◽

10.1161/hyp.60.suppl_1.a655 ◽

2012 ◽

Vol 60 (suppl_1) ◽

Author(s):

Duska Dragun ◽

Uwe Hoff ◽

Maximilian Blum ◽

Gordana Bubalo ◽

Mandy Fechner ◽

...

Keyword(s):

Acute Kidney Injury ◽

Creatinine Clearance ◽

Ischemia Reperfusion ◽

Kidney Injury ◽

Female Rats ◽

Epoxyeicosatrienoic Acid ◽

Renal Protection ◽

Sham Control ◽

Male And Female ◽

Enhanced Production

Females are naturally protected against ischemia/reperfusion (I/R)-induced acute kidney injury (AKI) in various clinical and experimental settings. However, the underlying mechanisms are unknown. We hypothesized that female protection may be conferred by enhanced production of cytochrome P450 (CYP)-dependent epoxyeicosatrienoic acids (EETs) that promote vasodilation as well as antiinflammatory and antiapoptotic pathways in the kidney. To test this hypothesis, we first analyzed the renal CYP-eicosanoid profile by liquid chromatography tandem mass spectrometry in male and female Lewis rats. Ischemia was induced through 45 min of left renal vessel clamping after right nephrectomy (n=6-8 per group). In non-ischemic controls, male and female kidneys stored almost identical amounts of EETs as well as 20-hydroxyeicosatetraenoic acid (20-HETE), both predominantly esterified into phospholipids, under basal non-ischemic conditions. 45 min of ischemia induced a massive release of EETs from membrane stores in females but not males. The free renal EET-levels reached 70.2±20.1 in females compared to only 4.6±1.3 ng/g in males. After ischemia, the ratio of free EETs to free 20-HETE was about 1:1 in females and 1:3 in males. Next, we proved the functional importance of EETs in renal protection by pretreating males with a synthetic EET-agonist (12-HUDE) and females with a selective EET-antagonist (14,15-EEZE-mSI). As analyzed two days after reperfusion, the EET-agonist protected males against loss of creatinine clearance (1.03±0.18 vs. 0.26±0.02 ml/min, p<0.01 vs. vehicle, compared to 1.28±0.06 ml/min in sham control). Females were rendered susceptible to I/R-injury by the EET-antagonist (creatinine clearance: 0.25±0.05 vs. 0.67±0.04; p<0.01 vs. vehicle, compared to 0.81±0.04 ml/min in sham control). Changes in inflammatory cell infiltration and tubular apoptosis paralleled these effects on renal function. Our results indicate that female rats are protected against renal I/R-injury by enhanced ischemia-induced EET-release and demonstrate that renal protection can be transferred to males using synthetic EET-agonists.

Download Full-text