scholarly journals Macrophages are not the source of injurious interleukin-18 in ischemic acute kidney injury in mice

2009 ◽  
Vol 296 (3) ◽  
pp. F535-F542 ◽  
Author(s):  
Zhibin He ◽  
Belda Dursun ◽  
Dong-Jin Oh ◽  
Lawrence Lu ◽  
Sarah Faubel ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Adoptive Transfer ◽  
Kidney Injury ◽  
Peritoneal Macrophages ◽  
Raw 264.7 Cells ◽  
Wild Type ◽  
Interleukin 18 ◽  
Caspase 1 ◽  
Outer Stripe ◽  
Ischemic Acute Kidney Injury

We previously reported in ischemic acute kidney injury (AKI) in mice that caspase-1-mediated production of interleukin-18 (IL-18) is pathogenic and that macrophage depletion by liposome-encapsulated clodronate (LEC) is protective. Therefore, our aim was to determine whether macrophages are a source of IL-18 in ischemic AKI in mice. On immunofluorescence staining of the outer stripe of outer medulla, the number of macrophages double stained for CD11b and IL-18 was significantly increased in AKI and significantly decreased by LEC. Adoptive transfer of RAW 264.7 cells, a mouse macrophage line that constitutively expresses IL-18 mRNA, reversed the functional protection against AKI in both LEC-treated wild-type and caspase-1 −/− mice. To test whether IL-18 in macrophages is necessary to cause AKI, we adoptively transferred macrophages in which IL-18 was inhibited. Peritoneal macrophages isolated from wild-type mice, IL-18 binding protein transgenic (IL-18 BP Tg) mice, and IL-18 −/− mice were used. IL-18 BP Tg mice overexpress human IL-18 BP and exhibit decreased biological activity of IL-18. Adoptive transfer of peritoneal macrophages from wild-type as well as IL-18 BP Tg and IL-18 −/− mice reversed the functional protection against AKI in LEC-treated mice. In summary, adoptive transfer of RAW cells, that constitutively express IL-18, reverses the functional protection in macrophage-depleted wild-type and caspase-1 −/− mice with AKI. However, adoptive transfer of peritoneal macrophages in which IL-18 function was inhibited also reverses the functional protection in macrophage-depleted mice. In conclusion, IL-18 from adoptive transfer of macrophages is not sufficient to cause ischemic AKI.

scholarly journals Interleukin-18 binding protein transgenic mice are protected against ischemic acute kidney injury

2008 ◽  
Vol 295 (5) ◽  
pp. F1414-F1421 ◽  
Author(s):  
Zhibin He ◽  
Lawrence Lu ◽  
Christopher Altmann ◽  
Thomas S. Hoke ◽  
Danica Ljubanovic ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Binding Protein ◽  
Kidney Injury ◽  
Macrophage Infiltration ◽  
Colony Stimulating Factor ◽  
Wild Type ◽  
Macrophage Colony Stimulating Factor ◽  
Ischemic Acute Kidney Injury ◽  
Macrophage Colony ◽  
Stimulating Factor

IL-18 function is neutralized in IL-18 binding protein transgenic (IL-18BP Tg) mice. First, we determined whether IL-18BP Tg mice are protected against ischemic acute kidney injury (AKI). Ischemic AKI was induced by bilateral renal pedicle clamping. IL-18BP Tg mice were functionally and histologically protected against ischemic AKI as determined by blood urea nitrogen, serum creatinine, and acute tubular necrosis score. We have demonstrated that the injurious effect of IL-18 in the kidney is independent of neutrophils and lymphocytes. Thus the effect of IL-18 inhibition on renal macrophage infiltration was determined. The number of macrophages was significantly reduced in IL-18BP Tg compared with wild-type kidneys. To determine the cytokines and chemokines that are dependent on IL-18, we performed flow cytometry based assays. Multiple chemokines/cytokines, IL-3, IL-6, IL-15, IL-18, leukemia inhibitory factor, macrophage colony-stimulating factor, macrophage inflammatory protein-2, granulocyte-macrophage colony-stimulating factor, and monocyte chemotactic protein-1 were significantly increased in AKI vs. sham kidneys. Only CXCL1 (also known as KC or IL-8) was significantly increased in AKI vs. sham kidneys and significantly reduced in IL-18BP Tg AKI vs. wild-type AKI kidneys. To determine whether macrophages are the source of CXCL1 in the kidney, we depleted macrophages with liposomal encapsulated clodronate. CXCL1 was significantly decreased in macrophage-depleted vs. control AKI mice. In summary, in ischemic AKI in mice, 1) IL-18BP Tg mice are functionally and histologically protected, 2) macrophage infiltration in the kidney and CXCL1 are significantly reduced in IL-18BP Tg mice, and 3) macrophage depletion significantly reduces CXCL1 in the kidney. In conclusion, protection against ischemic AKI in IL-18BP Tg mice is associated with less macrophage infiltration and less production of CXCL1 in the kidney.

scholarly journals Caspase-1-Inhibitor AC-YVAD-CMK Inhibits Pyroptosis and Ameliorates Acute Kidney Injury in a Model of Sepsis

2021 ◽  
Vol 2021 ◽  
pp. 1-9
Author(s):  
Mei Yang ◽  
Jin-tao Fang ◽  
Ni-shang Zhang ◽  
Long-jiang Qin ◽  
Yang-yang Zhuang ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Cecal Ligation ◽  
Kidney Tissue ◽  
Kidney Injury ◽  
Serum Levels ◽  
Interleukin 18 ◽  
Tissue Samples ◽  
Caspase 1 ◽  
Tnf Α ◽  
Histologic Changes

Objective. To observe the protective effect of AC-YVAD-CMK on sepsis-induced acute kidney injury in mice and to explore its possible mechanisms primarily. Methods. Eighteen male C57BL/6 mice were randomly divided into sham-operated group (Control), cecal ligation and puncture group (CLP), and CLP model treated with AC-YVAD-CMK group (AC-YVAD-CMK) ( n = 6 in each group). Mice were sacrificed at 24 h after operation, and blood and kidney tissue samples were collected for analyses. Histologic changes were determined microscopically following HE staining. The expression of Ly-6B and CD68 was investigated using immunohistochemistry. Serum concentrations of creatinine (sCR) and blood urea nitrogen (BUN) were measured. Serum levels of interleukin-1β (IL-1β), interleukin-18 (IL-18), TNF-α, and interleukin-6 (IL-6) were determined by ELISA. The expressions of Caspas-1, NLRP-1, IL-1β, and IL-18 in renal tissues were investigated using Western blot. Immunofluorescence staining was used to detect the expression of GSDMD protein in renal tissues. Results. AC-YVAD-CMK treatment significantly alleviates sepsis-induced acute kidney injury, with decreased histological injury in renal tissues, suppresses the accumulation of neutrophils and macrophages in renal tissues, and decreased sCR and BUN level ( P < 0.05 ). Attenuation of sepsis-induced acute kidney injury was due to the prohibited production of inflammatory cytokines and decrease expression of Caspas-1, NLRP-1, IL-1β, and IL-18 in renal tissues. In addition, AC-YVAD-CMK treatment significantly reduced the expression of GSDMD in renal tissues compared to those observed in controls ( P < 0.05 ). Conclusions. We demonstrated a marked renoprotective effect of caspase-1-inhibitor AC-YVAD-CMK in a rat model of sepsis by inhibition of pyroptosis.

scholarly journals A1 adenosine receptor allosteric enhancer PD-81723 protects against renal ischemia-reperfusion injury

2012 ◽  
Vol 303 (5) ◽  
pp. F721-F732 ◽  
Author(s):  
Sang Won Park ◽  
Joo Yun Kim ◽  
Ahrom Ham ◽  
Kevin M. Brown ◽  
Mihwa Kim ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Side Effects ◽  
Proximal Tubule ◽  
Ischemia Reperfusion ◽  
Kidney Injury ◽  
Wild Type ◽  
Renal Protection ◽  
Ischemic Acute Kidney Injury ◽  
Renal Tubular ◽  
Deficient Mice

Activation of A1 adenosine receptors (ARs) protects against renal ischemia-reperfusion (I/R) injury by reducing necrosis, apoptosis, and inflammation. However, extrarenal side effects (bradycardia, hypotension, and sedation) may limit A1AR agonist therapy for ischemic acute kidney injury. Here, we hypothesized that an allosteric enhancer for A1AR (PD-81723) protects against renal I/R injury without the undesirable side effects of systemic A1AR activation by potentiating the cytoprotective effects of renal adenosine generated locally by ischemia. Pretreatment with PD-81723 produced dose-dependent protection against renal I/R injury in A1AR wild-type mice but not in A1AR-deficient mice. Significant reductions in renal tubular necrosis, neutrophil infiltration, and inflammation as well as tubular apoptosis were observed in A1AR wild-type mice treated with PD-81723. Furthermore, PD-81723 decreased apoptotic cell death in human proximal tubule (HK-2) cells in culture, which was attenuated by a specific A1AR antagonist (8-cyclopentyl-1,3-dipropylxanthine). Mechanistically, PD-81723 induced sphingosine kinase (SK)1 mRNA and protein expression in HK-2 cells and in the mouse kidney. Supporting a critical role of SK1 in A1AR allosteric enhancer-mediated renal protection against renal I/R injury, PD-81723 failed to protect SK1-deficient mice against renal I/R injury. Finally, proximal tubule sphingosine-1-phosphate type 1 receptors (S1P1Rs) are critical for PD-81723-induced renal protection, as mice selectively deficient in renal proximal tubule S1P1Rs (S1P1Rflox/flox PEPCKCre/− mice) were not protected against renal I/R injury with PD-81723 treatment. Taken together, our experiments demonstrate potent renal protection with PD-81723 against I/R injury by reducing necrosis, inflammation, and apoptosis through the induction of renal tubular SK1 and activation of proximal tubule S1P1Rs. Our findings imply that selectively enhancing A1AR activation by locally produced renal adenosine may be a clinically useful therapeutic option to attenuate ischemic acute kidney injury without systemic side effects.

scholarly journals Critical Role of Interleukin-11 in Isoflurane-mediated Protection against Ischemic Acute Kidney Injury in Mice

2013 ◽  
Vol 119 (6) ◽  
pp. 1389-1401 ◽  
Author(s):  
Ahrom Ham ◽  
Mihwa Kim ◽  
Joo Yun Kim ◽  
Kevin M. Brown ◽  
James Yeh ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Kidney Injury ◽  
Neutralizing Antibody ◽  
Wild Type ◽  
Proximal Tubule Cells ◽  
Carrier Gas ◽  
Tubule Cells ◽  
Ischemic Acute Kidney Injury ◽  
Renal Tubular ◽  
Tgf Β1

Abstract Background: Isoflurane releases renal tubular transforming growth factor-β1 (TGF-β1) and protects against ischemic acute kidney injury. Recent studies suggest that TGF-β1 can induce a cytoprotective cytokine interleukin (IL)-11. In this study, the authors tested the hypothesis that isoflurane protects against ischemic acute kidney injury by direct induction of renal tubular IL-11 synthesis. Methods: Human kidney proximal tubule cells were treated with 1.25–2.5% isoflurane or carrier gas (room air + 5% carbon dioxide) for 0–16 h. The authors also anesthetized C57BL/6 mice with 1.2% isoflurane or with equianesthetic dose of pentobarbital for 4 h. In addition, the authors subjected IL-11 receptor (IL-11R) wild-type, IL-11R–deficient, or IL-11 neutralized mice to 30-min renal ischemia followed by reperfusion under 4 h of anesthesia with pentobarbital or isoflurane (1.2%). Results: Isoflurane increased IL-11 synthesis in human (approximately 300–500% increase, N = 6) and mouse (23 ± 4 [mean ± SD] fold over carrier gas group, N = 4) proximal tubule cells that were attenuated by a TGF-β1–neutralizing antibody. Mice anesthetized with isoflurane showed significantly increased kidney IL-11 messenger RNA (13.8 ± 2 fold over carrier gas group, N = 4) and protein (31 ± 9 vs. 18 ± 2 pg/mg protein or approximately 80% increase, N = 4) expression compared with pentobarbital-anesthetized mice, and this increase was also attenuated by a TGF-β1–neutralizing antibody. Furthermore, isoflurane-mediated renal protection in IL-11R wild-type mice was absent in IL-11R–deficient mice or in IL-11R wild-type mice treated with IL-11–neutralizing antibody (N = 4–6). Conclusion: In this study, the authors suggest that isoflurane induces renal tubular IL-11 via TGF-β1 signaling to protect against ischemic acute kidney injury.

scholarly journals Thioredoxin-Interacting Protein Mediates NLRP3 Inflammasome Activation Involved in the Susceptibility to Ischemic Acute Kidney Injury in Diabetes

2016 ◽  
Vol 2016 ◽  
pp. 1-17 ◽  
Author(s):  
Ye Da Xiao ◽  
Ya Yi Huang ◽  
Hua Xin Wang ◽  
Yang Wu ◽  
Yan Leng ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Kidney Injury ◽  
Diabetic Rats ◽  
Daily Injection ◽  
Inflammasome Activation ◽  
Interacting Protein ◽  
Thioredoxin Interacting Protein ◽  
Caspase 1 ◽  
Ischemic Acute Kidney Injury ◽  
The Impact

Kidney in diabetic state is more sensitive to ischemic acute kidney injury (AKI). However, the underlying mechanisms remain unclear. Herein, we examined the impact of diabetes mellitus on thioredoxin-interacting protein (TXNIP) expression and whether mediated NLRP3 activation was associated with renal ischemia/reperfusion- (I/R-) induced AKI. In an in vivo model, streptozotocin-induced diabetic rats showed higher susceptibility to I/R injury with increased TXNIP expression, which was significantly attenuated by resveratrol (RES) treatment (10 mg/kg intraperitoneal daily injection for 7 consecutive days prior to I/R induction). RES treatment significantly inhibited TXNIP binding to NLRP3 in diabetic rats subjected to renal I/R injury. Furthermore, RES treatment significantly reduced cleaved caspase-1 expression and production of IL-1β and IL-18. In an in vitro study using cultured human kidney proximal tubular cell (HK-2 cells) in high glucose condition (HG, 30 mM) subjected to hypoxia/reoxygenation (H/R), HG combined H/R (HH/R) stimulated TXNIP expression which was accompanied by increased NLRP3 expression, ROS generation, caspase-1 activity and IL-1β levels, and aggravated HK-2 cells apoptosis. All these changes were significantly attenuated by TXNIP RNAi and RES treatment. In conclusion, our results demonstrate that TXNIP-mediated NLRP3 activation through oxidative stress is a key signaling mechanism in the susceptibility to AKI in diabetic models.

scholarly journals Proximal tubule-specific overexpression of netrin-1 suppresses acute kidney injury-induced interstitial fibrosis and glomerulosclerosis through suppression of IL-6/STAT3 signaling

2013 ◽  
Vol 304 (8) ◽  
pp. F1054-F1065 ◽  
Author(s):  
Punithavathi Ranganathan ◽  
Calpurnia Jayakumar ◽  
Ganesan Ramesh
Keyword(s):  
Acute Kidney Injury ◽  
Epithelial Cells ◽  
Interstitial Fibrosis ◽  
Kidney Injury ◽  
Transgenic Animals ◽  
Acute Injury ◽  
Tubular Epithelial Cells ◽  
Wild Type ◽  
Proximal Tubular Epithelial Cells ◽  
Proximal Tubular

Acute kidney injury-induced organ fibrosis is recognized as a major risk factor for the development of chronic kidney disease, which remains one of the leading causes of death in the developed world. However, knowledge on molecules that may suppress the fibrogenic response after injury is lacking. In ischemic models of acute kidney injury, we demonstrate a new function of netrin-1 in regulating interstitial fibrosis. Acute injury was promptly followed by a rise in serum creatinine in both wild-type and netrin-1 transgenic animals. However, the wild-type showed a slow recovery of kidney function compared with netrin-1 transgenic animals and reached baseline by 3 wk. Histological examination showed increased infiltration of interstitial macrophages, extensive fibrosis, reduction of capillary density, and glomerulosclerosis. Collagen IV and α-smooth muscle actin expression was absent in sham-operated kidneys; however, their expression was significantly increased at 2 wk and peaked at 3 wk after reperfusion. These changes were reduced in the transgenic mouse kidney, which overexpresses netrin-1 in proximal tubular epithelial cells. Fibrosis was associated with increased expression of IL-6 and extensive and chronic activation of STAT3. Administration of IL-6 exacerbated fibrosis in vivo in wild-type, but not in netrin-1 transgenic mice kidney and increased collagen I expression and STAT3 activation in vitro in renal epithelial cells subjected to hypoxia-reoxygenation, which was suppressed by netrin-1. Our data suggest that proximal tubular epithelial cells may play a prominent role in interstitial fibrosis and that netrin-1 could be a useful therapeutic agent for treating kidney fibrosis.

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