scholarly journals Unexpected Participation of Intercalated Cells in Renal Inflammation and Acute Kidney Injury

Nephron ◽  
2021 ◽  
pp. 1-6
Author(s):  
Sylvie Breton ◽  
Maria Agustina Battistone
Keyword(s):  
Acute Kidney Injury ◽  
Purinergic Receptor ◽  
Collecting Duct ◽  
Ischemia Reperfusion ◽  
Kidney Injury ◽  
Sterile Inflammation ◽  
Medical Complication ◽  
Apical Surface ◽  
Intercalated Cells ◽  
Pathogen Defense

Epithelial cells constitute the 1st line of defense against pathogens, and their participation in innate immunity is rapidly emerging. In this mini-review, we discuss the noncanonical role of renal intercalated cells (ICs) in pathogen defense and in the initiation of sterile inflammation. This last function has strong implications in the onset of acute kidney injury (AKI), a potentially fatal medical complication that is seen in hospitalized patients. AKI is associated with inflammation, and it is often diagnosed only after the kidneys have suffered significant and often irreversible damage. While examining the regulation of proton secretion by type A ICs (A-ICs), we unexpectedly found high expression of the pro-inflammatory purinergic receptor P2Y14 in these cells. This receptor is located on the apical surface of A-ICs and binds UDP-glucose (UDP-Glc), a danger-associated molecular pattern molecule released from injured cells that is filtered by the glomeruli and is concentrated in the collecting duct lumen. UDP-Glc activates P2Y14 in A-ICs and triggers the production of chemokines that attract pro-inflammatory immune cells into the kidney stroma and aggravate ischemia-induced proximal tubule injury. Inhibition of P2Y14 or deletion of its gene specifically in ICs in a murine model of ischemia-reperfusion injury attenuated these effects. Thus, together with their previously recognized role in pathogen defense, A-ICs are now recognized as sensors and mediators of renal sterile inflammation that participate in the onset of AKI. Blocking the UDP-Glc/P2Y14 pathway in A-ICs provides new insights into the development of novel AKI therapeutics.

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

2017 ◽  
Vol 37 (22) ◽  
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.

scholarly journals C-type lectin Mincle mediates cell death–triggered inflammation in acute kidney injury

2020 ◽  
Vol 217 (11) ◽  
Author(s):  
Miyako Tanaka ◽  
Marie Saka-Tanaka ◽  
Kozue Ochi ◽  
Kumiko Fujieda ◽  
Yuki Sugiura ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Cell Death ◽  
Free Cholesterol ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Kidney Injury ◽  
Sterile Inflammation ◽  
Renal Tubular Cell ◽  
Renal Tubules ◽  
Underlying Mechanisms

Accumulating evidence indicates that cell death triggers sterile inflammation and that impaired clearance of dead cells causes nonresolving inflammation; however, the underlying mechanisms are still unclear. Here, we show that macrophage-inducible C-type lectin (Mincle) senses renal tubular cell death to induce sustained inflammation after acute kidney injury in mice. Mincle-deficient mice were protected against tissue damage and subsequent atrophy of the kidney after ischemia–reperfusion injury. Using lipophilic extract from the injured kidney, we identified β-glucosylceramide as an endogenous Mincle ligand. Notably, free cholesterol markedly enhanced the agonistic effect of β-glucosylceramide on Mincle. Moreover, β-glucosylceramide and free cholesterol accumulated in dead renal tubules in proximity to Mincle-expressing macrophages, where Mincle was supposed to inhibit clearance of dead cells and increase proinflammatory cytokine production. This study demonstrates that β-glucosylceramide in combination with free cholesterol acts on Mincle as an endogenous ligand to induce cell death–triggered, sustained inflammation after acute kidney injury.

scholarly journals Post-treatment with JP-1302 protects against renal ischemia/reperfusion-induced acute kidney injury in rats

2019 ◽  
Vol 139 (3) ◽  
pp. 137-142 ◽  
Author(s):  
Takaomi Shimokawa ◽  
Hidenobu Tsutsui ◽  
Takeshi Miura ◽  
Masashi Takama ◽  
Kohei Hayashi ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Ischemia Reperfusion ◽  
Kidney Injury ◽  
Post Treatment ◽  
Renal Ischemia

scholarly journals Comment on “Nuclear receptor PXR targets AKR1B7 to protect mitochondrial metabolism and renal function in AKI”

2021 ◽  
Vol 13 (593) ◽  
pp. eabd0214
Author(s):  
Zhilin Luan ◽  
Wenhua Ming ◽  
Cong Zhang ◽  
Xiaoxiao Huo ◽  
Feng Zheng ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Renal Function ◽  
Nuclear Receptor ◽  
Ischemia Reperfusion ◽  
Kidney Injury ◽  
Pregnane X Receptor ◽  
Mitochondrial Metabolism

The nuclear pregnane X receptor may not protect against ischemia/reperfusion-induced acute kidney injury in mice.

MO343SERUM RESPONSE FACTOR, A NOVEL EARLY DIAGNOSTIC BIOMARKER OF ACUTE KIDNEY INJURY

2021 ◽  
Vol 36 (Supplement_1) ◽  
Author(s):  
Long Zhao ◽  
Yan Xu
Keyword(s):  
Acute Kidney Injury ◽  
Serum Response Factor ◽  
Ischemia Reperfusion ◽  
Kidney Injury ◽  
Diagnostic Value ◽  
Renal Tissue ◽  
Response Factor ◽  
Diagnostic Biomarker ◽  
Renal Tubular ◽  
Early Diagnostic

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.

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

2018 ◽  
Vol 25 (6) ◽  
pp. 73-77 ◽  
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.

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

Biology Open ◽  
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.

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