scholarly journals AT1 and AT2 receptors modulate renal tubular cell necroptosis in angiotensin II-infused renal injury mice

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Yongjun Zhu ◽  
Hongwang Cui ◽  
Jie Lv ◽  
Haiqin Liang ◽  
Yanping Zheng ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Renal Injury ◽  
Critical Role ◽  
Kidney Injury ◽  
Renin Angiotensin System ◽  
Tubular Cell ◽  
Tubular Damage ◽  
Renal Tubular Cell ◽  
Ang Ii ◽  
Renal Tubular

AbstractAbnormal renin-angiotensin system (RAS) activation plays a critical role in the initiation and progression of chronic kidney disease (CKD) by directly mediating renal tubular cell apoptosis. Our previous study showed that necroptosis may play a more important role than apoptosis in mediating renal tubular cell loss in chronic renal injury rats, but the mechanism involved remains unknown. Here, we investigate whether blocking the angiotensin II type 1 receptor (AT1R) and/or angiotensin II type 2 receptor (AT2R) beneficially alleviates renal tubular cell necroptosis and chronic kidney injury. In an angiotensin II (Ang II)-induced renal injury mouse model, we found that blocking AT1R and AT2R effectively mitigates Ang II-induced increases in necroptotic tubular epithelial cell percentages, necroptosis-related RIP3 and MLKL protein expression, serum creatinine and blood urea nitrogen levels, and tubular damage scores. Furthermore, inhibition of AT1R and AT2R diminishes Ang II-induced necroptosis in HK-2 cells and the AT2 agonist CGP42112A increases the percentage of necroptotic HK-2 cells. In addition, the current study also demonstrates that Losartan and PD123319 effectively mitigated the Ang II-induced increases in Fas and FasL signaling molecule expression. Importantly, disruption of FasL significantly suppressed Ang II-induced increases in necroptotic HK-2 cell percentages, and necroptosis-related proteins. These results suggest that Fas and FasL, as subsequent signaling molecules of AT1R and AT2R, might involve in Ang II-induced necroptosis. Taken together, our results suggest that Ang II-induced necroptosis of renal tubular cell might be involved both AT1R and AT2R and the subsequent expression of Fas, FasL signaling. Thus, AT1R and AT2R might function as critical mediators.

scholarly journals Knockout of TRPA1 exacerbates angiotensin II-induced kidney injury

2019 ◽  
Vol 317 (3) ◽  
pp. F623-F631 ◽  
Author(s):  
Shuangtao Ma ◽  
Yan Zhang ◽  
Kecheng He ◽  
Peijian Wang ◽  
Donna H. Wang
Keyword(s):  
Angiotensin Ii ◽  
Renal Injury ◽  
Transient Receptor Potential ◽  
Critical Role ◽  
Kidney Injury ◽  
Receptor Potential ◽  
Protective Role ◽  
Ang Ii ◽  
Arginase 1 ◽  
Induced Apoptosis

Macrophage-mediated inflammation plays a critical role in hypertensive kidney disease. Here, we investigated the role of transient receptor potential ankyrin 1 (TRPA1), a sensor of inflammation, in angiotensin II (ANG II)-induced renal injury. Subcutaneous infusion of ANG II (600 ng·min−1·kg−1) for 28 days was used to induce hypertension and renal injury in mice. The results showed that ANG II-induced hypertensive mice have decreased renal Trpa1 expression ( P < 0.01), whereas ANG II receptor type 1a-deficient hypotensive mice have increased renal Trpa1 expression ( P < 0.05) compared with their normotensive counterparts. ANG II induced similar elevations of systolic blood pressure in Trpa1−/− and wild-type (WT) mice but led to higher levels of blood urea nitrogen ( P < 0.05), serum creatinine ( P < 0.05), and renal fibrosis ( P < 0.01) in Trpa1−/− mice than WT mice. Similarly, ANG II increased both CD68+/inducible nitric oxide synthase+ M1 and CD68+/arginase 1+ M2 macrophages in the kidneys of both Trpa1−/− and WT mice (all P < 0.01), with higher extents in Trpa1−/− mice (both P < 0.01). Compared with WT mice, Trpa1−/− mice had significantly increased expression levels of inflammatory cytokines and their receptors in the kidney. Cultured murine macrophages were stimulated with phorbol 12-myristate 13-acetate, which downregulated gene expression of TRPA1 ( P < 0.01). A TRPA1 agonist, cinnamaldehyde, significantly inhibited phorbol 12-myristate 13-acetate-stimulated expression of IL-1β and chemokine (C-C motif) ligand 2 in macrophages, which were attenuated by pretreatment with a TRPA1 antagonist, HC030031 . Furthermore, activation of TRPA1 with cinnamaldehyde induced apoptosis of macrophages. These findings suggest that TRPA1 may play a protective role in ANG II-induced renal injury, likely through inhibiting macrophage-mediated inflammation.

scholarly journals NIX-mediated mitophagy protects against proteinuria-induced tubular cell apoptosis and renal injury

2019 ◽  
Vol 316 (2) ◽  
pp. F382-F395 ◽  
Author(s):  
Dan Xu ◽  
Panpan Chen ◽  
Bao Wang ◽  
Yanzhe Wang ◽  
Naijun Miao ◽  
...  
Keyword(s):  
Renal Injury ◽  
Cell Apoptosis ◽  
Cell Injury ◽  
Kidney Injury ◽  
Underlying Mechanism ◽  
Tubular Cell ◽  
Renal Tubular Cell ◽  
Common Symptom ◽  
Renal Tubules ◽  
Renal Tubular

Proteinuria, the most common symptom of renal injury, is an independent factor for renal tubular injury. However, the underlying mechanism remains to be fully elucidated. Mitochondrion is an important target for proteinuria-induced renal tubular cell injury. Insufficient mitophagy exacerbates cell injury by initiating mitochondrial dysfunction-related cell apoptosis. In the experiment, the role of NIP3-like protein X (NIX)-mediated mitophagy was investigated in proteinuria-induced renal injury. In this study, we demonstrated that NIX expression was reduced in renal tubules and correlated with the decline of estimated glomerular filtration rate and increase of the proteinuria in patients. In proteinuric mice, NIX-mediated mitophagy was significantly suppressed. Meanwhile, the proteinuric mice exhibited renal dysfunction, increased mitochondrial fragmentation, and tubular cell apoptosis. Overexpression of NIX attenuated those disruptions in proteinuric mice. In cultured renal tubular epithelial cells, albumin induced a decrease in NIX-mediated mitophagy and an increase in cell apoptosis. Overexpression of NIX attenuated albumin-induced cell apoptosis, whereas NIX siRNA aggravated these perturbations. These results indicate that proteinuria suppresses NIX-mediated mitophagy in the renal tubular epithelial cell, which triggers the cell undergoing mitochondria-dependent cell apoptosis. Collectively, our finding suggests that restoration of NIX-mediated mitophagy might be a novel therapeutic target for alleviating proteinuria-induced kidney injury.

scholarly journals Intrarenal activation of adaptive immune effectors is associated with tubular damage and impaired renal function in lupus nephritis

2018 ◽  
Vol 77 (12) ◽  
pp. 1782-1789 ◽  
Author(s):  
Cristina Pamfil ◽  
Zuzanna Makowska ◽  
Aurélie De Groof ◽  
Gaëlle Tilman ◽  
Sepideh Babaei ◽  
...  
Keyword(s):  
Renal Function ◽  
Lupus Nephritis ◽  
Cell Activation ◽  
Immune Cell ◽  
Tubular Cell ◽  
Tubular Damage ◽  
Renal Tubular Cell ◽  
Chronic Renal Impairment ◽  
Adaptive Immune ◽  
Renal Tubular

ObjectivesChronic renal impairment remains a feared complication of lupus nephritis (LN). The present work aimed at identifying mechanisms and markers of disease severity in renal tissue samples from patients with LN.MethodsWe performed high-throughput transcriptomic studies (Illumina HumanHT-12 v4 Expression BeadChip) on archived kidney biopsies from 32 patients with LN and eight controls (pretransplant donors). Histological staging (glomerular and tubular scores) and immunohistochemistry experiments were performed on the same and on a replication set of 37 LN kidney biopsy samples.ResultsA group of LN samples was identified by unsupervised clustering studies based on their gene expression features, that is, the overexpression of transcripts involved in antigen presentation, T and B cell activation. These samples were characterised by a significantly lower estimated glomerular filtration rate (eGFR) at the time of biopsy (T0) compared with the other systemic lupus erythematosus samples. Yet, apparent disease duration at T0, double-stranded DNA antibody titres at T0 and other relevant characteristics (serum C3, proteinuria, histological scores, numbers of previous flares) were not different between groups.Immunohistochemistry studies confirmed the association between interstitial infiltration by adaptive immune effectors and decreased renal function in the same and in a replication group of LN kidney biopsies. This was associated with transcriptomic, histological and immunohistochemical evidence of renal tubular cell involvement.ConclusionInterstitial infiltration of LN kidney biopsies by adaptive immune effectors is associated with impaired renal tubular cell function and decreased eGFR. These results open new perspectives in evaluating and treating patients with LN, focusing on intrarenal mechanisms of immune cell activation.

scholarly journals Class IIa HDAC inhibitor TMP195 alleviates lipopolysaccharide-induced acute kidney injury

2020 ◽  
Vol 319 (6) ◽  
pp. F1015-F1026
Author(s):  
Wei Zhang ◽  
Yinjie Guan ◽  
George Bayliss ◽  
Shougang Zhuang
Keyword(s):  
Acute Kidney Injury ◽  
Hdac Inhibitor ◽  
Cell Apoptosis ◽  
Kidney Injury ◽  
Tubular Cell ◽  
Intercellular Adhesion Molecule ◽  
Renal Tubular Cell ◽  
Renoprotective Effect ◽  
Renal Tubular ◽  
Class Iia Hdacs

Sepsis-associated acute kidney injury (SA-AKI) is associated with high mortality rates, but clinicians lack effective treatments except supportive care or renal replacement therapies. Recently, histone deacetylase (HDAC) inhibitors have been recognized as potential treatments for acute kidney injury and sepsis in animal models; however, the adverse effect generated by the use of pan inhibitors of HDACs may limit their application in people. In the present study, we explored the possible renoprotective effect of a selective class IIa HDAC inhibitor, TMP195, in a murine model of SA-AKI induced by lipopolysaccharide (LPS). Administration of TMP195 significantly reduced increased serum creatinine and blood urea nitrogen levels and renal damage induced by LPS; this was coincident with reduced expression of HDAC4, a major isoform of class IIa HDACs, and elevated histone H3 acetylation. TMP195 treatment following LPS exposure also reduced renal tubular cell apoptosis and attenuated renal expression of neutrophil gelatinase-associated lipocalin and kidney injury molecule-1, two biomarkers of tubular injury. Moreover, LPS exposure resulted in increased expression of BAX and cleaved caspase-3 and decreased expression of Bcl-2 and bone morphogenetic protein-7 in vivo and in vitro; TMP195 treatment reversed these responses. Finally, TMP195 inhibited LPS-induced upregulation of multiple proinflammatory cytokines/chemokines, including intercellular adhesion molecule-1, monocyte chemoattractant protein-1, tumor necrosis factor-α, and interleukin-1β, and accumulation of inflammatory cells in the injured kidney. Collectively, these data indicate that TMP195 has a powerful renoprotective effect in SA-AKI by mitigating renal tubular cell apoptosis and inflammation and suggest that targeting class IIa HDACs might be a novel therapeutic strategy for the treatment of SA-AKI that avoids the unintended adverse effects of a pan-HDAC inhibitor.

scholarly journals Angiotensin II Upregulates Sodium-Glucose Co-Transporter2 (SGLT2) Expression and SGLT2 Inhibitor Attenuates Ang II-Induced Hypertensive Renal Injury in Mice

2020 ◽  
Author(s):  
Kana N Miyata ◽  
Chao-Sheng Lo ◽  
Shuiling Zhao ◽  
Min-Chun Liao ◽  
Yuchao Pang ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Renal Injury ◽  
Linear Regression Analysis ◽  
Sglt2 Inhibitor ◽  
Renin Angiotensin System ◽  
Mrna Levels ◽  
Ang Ii ◽  
Multivariable Linear Regression Analysis ◽  
Renal Proximal Tubular Cells

Clinical trials indicate that sodium-glucose co-transporter 2 inhibitors (SGLT2i) improve kidney function, yet, the molecular regulation of SGLT2 expression is incompletely understood. Here, we investigated the role of the intrarenal renin-angiotensin-system (RAS) on SGLT2 expression. In adult non-diabetic participants in the Nephrotic Syndrome Study Network (NEPTUNE, N=163), multivariable linear regression analysis showed SGLT2 mRNA was significantly associated with angiotensinogen (AGT), renin, and angiotensin converting enzyme (ACE) mRNA levels (p&lt;0.001). In vitro, angiotensin II (Ang II) dose-dependently stimulated SGLT2 expression in HK-2, human immortalized renal proximal tubular cells (RPTCs); losartan and antioxidants inhibited it. Sglt2 expression was increased in transgenic mice specifically overexpressing Agt in their RPTCs, as well as in WT mice with a single subcutaneous injection of Ang II (1.44 mg/kg). Moreover, Ang II (1000 ng/kg/min) infusion via osmotic mini-pump in WT mice for 4 weeks increased systolic blood pressure (SBP), glomerulosclerosis, tubulointerstitial fibrosis, and albuminuria; canaglifozin (Cana, 15 mg/kg/day) reversed these changes, with the exception of SBP. Fractional glucose excretion was higher in Ang II+Cana than WT+Cana, whereas Sglt2 expression was similar. Our data demonstrate a link between intrarenal RAS and SGLT2 expression and that SGLT2i ameliorates Ang II-induced renal injury independent of SBP.

Abstract 514: Jak2 Tyrosine Kinase Mediates Angiotensin II Renal Pathogenesis via its Pressor Dependent Actions

Hypertension ◽  
2014 ◽  
Vol 64 (suppl_1) ◽  
Author(s):  
Peter P Sayeski ◽  
Sung O Park ◽  
Annet Kirabo ◽  
Rebekah Baskin ◽  
Dale M Seth ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Renal Injury ◽  
Interstitial Fibrosis ◽  
Critical Role ◽  
Glomerular Sclerosis ◽  
Control Group ◽  
Mrna Levels ◽  
Ang Ii ◽  
Urine Albumin ◽  
Independent Events

We previously found that Jak2 kinase, expressed within vascular smooth muscle cells (VSMC), plays a critical role in angiotensin II (Ang II)-mediated hypertension. Given that Jak2 mediates both pressor-dependent and pressor-independent events, we sought to determine the role of blood pressure (BP), per se, on the deleterious effects of Jak2 within the kidney. To investigate this, three groups of mice were examined; i) wild type mice (Controls) that received Ang II infusion, ii) mice lacking Jak2 expression within the VSMC (VSMC Jak2 Null) that also received Ang II, and iii) Control mice that received Ang II plus an anti-hypertensive triple therapy (3Rx). After baseline BP recordings, Ang II was infused (1000 ng/kg/min, SC) to all groups and the 3Rx regimen (80 mg/L hydralazine, 5 mg/L reserpine, 30 mg/L hydrochlorothiazide in the drinking water) was initiated two days later to the 3Rx group, in order to maintain BP at similar levels to the VSMC Jak2 Null group. After 28 days of Ang II, mice were euthanized and the kidneys were assessed via histological, molecular, and functional approaches. Chronic Ang II infusion significantly increased the levels of intrarenal Ang II in all three groups; Control = 1,262±283 fmol/g, VSMC Jak2 Null = 1,655±666 fmol/g, and 3Rx = 2,174±588. While Ang II infusion significantly increased the mean BP in the Control group (152 ± 2 mm Hg), it was significantly, and similarly, lower in both the VSMC Jak2 Null and 3Rx groups (125 ± 5 mm Hg and 131 ± 5 mm Hg, respectively). Glomerular sclerosis was absent and interstitial fibrosis ranged from absent- mild- moderate, and was similar in all groups. The increases in i) perivascular infiltration of CD3+ lymphocytes, ii) CTGF gene expression, iii) tubule casts and iv) albuminuria that were observed in the Control mice, were significantly reduced in both the VSMC Jak2 Null and 3Rx groups. [CTGF mRNA Levels: Control = 100%±17, VSMC Jak2 Null = 70%±12*, 3Rx= 56%±17*. Urine Albumin (ng/day): Control = 414 ± 262, VSMC Jak2 Null = 138 ± 172*, 3Rx= 101 ± 89* (*, p<0.05 vs. Control)]. Thus, the early renal injury due to chronic Ang II infusion correlates with increased BP and not with the expression of VSMC-derived Jak2, suggesting that Jak2 contributes to early Ang II-mediated renal injury via its pressor-dependent actions.

scholarly journals p53-cyclophilin D mediates renal tubular cell apoptosis in ischemia-reperfusion-induced acute kidney injury

2019 ◽  
Vol 317 (5) ◽  
pp. F1311-F1317 ◽  
Author(s):  
Huan Yang ◽  
Ruizhao Li ◽  
Li Zhang ◽  
Shu Zhang ◽  
Wei Dong ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Cell Death ◽  
Cell Apoptosis ◽  
Ischemia Reperfusion ◽  
Kidney Injury ◽  
Tubular Cell ◽  
Renal Tubular Cell ◽  
Cyclophilin D ◽  
Mptp Opening ◽  
Renal Tubular

Ischemia-reperfusion (I/R)-induced acute kidney injury (I/R-AKI) favors mitochondrial permeability transition pore (mPTP) opening and subsequent cell death. Cyclophilin D (CypD) is an essential component of the mPTP, and recent findings have implicated the p53-CypD complex in cell death. To evaluate the role of p53-CypD after I/R-AKI, we tested the hypothesis that the p53-CypD complex mediates renal tubular cell apoptosis in I/R-AKI via mPTP opening. Expression of p53 and cleaved caspase-3 was significantly increased in rats subjected to I/R-AKI compared with normal controls and sham-operated controls. The underlying mechanisms were determined using an in vitro model of ATP depletion. Inhibition of mPTP opening using the CypD inhibitor cyclosporin A or siRNA for p53 in ATP-depleted HK-2 cells prevented mitochondrial membrane depolarization and reduced apoptosis. Furthermore, p53 bound to CypD in ATP-depleted HK-2 cells. These results suggest that the p53-CypD complex mediates renal tubular cell apoptosis in I/R-AKI via mPTP opening.

The protective role of telmisartan against nephrotoxicity induced by X-ray contrast media in rat model

2009 ◽  
Vol 50 (7) ◽  
pp. 754-759 ◽  
Author(s):  
Shao Bin Duan ◽  
Yu Hui Wang ◽  
Fu You Liu ◽  
Xiang Qing Xu ◽  
Pian Wang ◽  
...  
Keyword(s):  
Serum Creatinine ◽  
Contrast Media ◽  
Renal Injury ◽  
Cell Apoptosis ◽  
Caspase 3 ◽  
Renal Tissue ◽  
Protective Role ◽  
Renal Tubular Cell ◽  
Ang Ii ◽  
Renal Tubular

Background: Contrast-induced nephropathy is a serious complication of diagnostic and interventional procedures. Purpose: To evaluate the nephrotoxicity of high- and low-osmolar contrast media (HOCM, LOCM) on kidneys in Sprague-Dawley rats. Telmisartan was administered to confirm its protective role against nephrotoxicity induced by contrast media. Material and Methods: Sixty male rats were randomly divided into six groups ( n=10/group). Glycerin was given to all rats except controls to induce renal injury. HOCM (diatrizoate) or LOCM (iohexol) (10 ml/kg b.w., 300 mg I/ml) was given through a caudal vein. Serum creatinine level was measured by an automatical biochemical analyzer. Caspase-3 activity and Angiotensin II (Ang II) level of renal tissue were detected by fluorometric method and radioimmunoassay, respectively. The renal injury was also assessed by hematoxylin and eosin and TdT-mediated deoxyuridine nick end-labeling staining. Results: In diatrizoate-injected rats, serum creatinine level was increased ( P<0.001). There was no significant difference between iohexol animals and glycerol controls in the level of serum creatinine. The renal caspase-3 activity and Ang II levels in HOCM and LOCM groups were higher than those in glycerol control group ( P<0.001). The percentage of apoptotic tubular cells and pathological scores were lower in the iohexol animals than that in the diatrizoate animals ( P<0.001). In the groups pretreated with telmisartan, no increase in the levels of serum creatinine, renal Ang II, and caspase-3 activity was observed ( P>0.05). The renal injuries induced by contrast media were alleviated. Conclusion: Both HOCM (diatrizoate) and LOCM (iohexol) could cause renal tubular cell apoptosis in the kidneys damaged by glycerin. LOCM was less toxic to rat kidneys than HOCM. Caspase-3 and Ang II might play a role in renal tubular cell apoptosis induced by contrast media. Telmisartan protected the renal tissue from nephrotoxicity induced by contrast media.

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