scholarly journals Blocking of interleukin-1 suppresses angiotensin II-induced renal injury

2021 ◽  
Vol 135 (17) ◽  
pp. 2035-2048
Author(s):  
Koji Akita ◽  
Kikuo Isoda ◽  
Fumie Ohtomo ◽  
Sarasa Isobe ◽  
Tomiharu Niida ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Renal Injury ◽  
Renal Damage ◽  
Interleukin 1 ◽  
Histological Change ◽  
Ang Ii ◽  
Glomerular Injury ◽  
Renal Inflammation ◽  
Clinical Hypertension ◽  
Renal Histology

Abstract Clinical hypertension (HT) is associated with renal inflammation and elevated circulating levels of proinflammatory cytokines. Interleukin (IL)-1 receptor antagonist (IL-1Ra) is one of the most important anti-inflammatory cytokines and plays a crucial role in inflammation. Inhibition of IL-1 may contribute to modulation of the Angiotensin II (Ang II)-induced HT response. The present study aimed to elucidate the effects of IL-1Ra and anti-IL-1β antibody (01BSUR) on Ang II-induced renal injury. To determine the contribution of IL-1Ra to Ang II-induced renal inflammation, male wildtype (WT) and IL-1Ra-deficient (IL-1Ra−/−) mice were infused with Ang II (1000 ng/kg/min) using subcutaneous osmotic pump for 14 days. We checked renal function, histological change, and several mRNA expressions 14 days after infusion. Fourteen days after infusion, systolic blood pressure (197 ± 5 vs 169 ± 9 mmHg, P<0.05) in IL-1Ra−/− mice significantly increased compared with WT mice. Furthermore, on day 14 of Ang II infusion, plasma IL-6 was 5.9-fold higher in IL-1Ra−/− versus WT mice (P<0.001); renal preproendothelin-1 mRNA expression was also significantly higher in IL-1Ra−/− mice (P<0.05). In addition, renal histology revealed greater damage in IL-1Ra−/− mice compared with WT mice 14 days after infusion. Finally, we administrated 01BSUR to both IL-1Ra−/− and WT mice, and 01BSUR treatment decreased Ang II-induced HT and renal damage (glomerular injury and fibrosis of the tubulointerstitial area) in both IL-1Ra−/− and WT mice compared with IgG2a treatment. Inhibition of IL-1 decreased Ang II-induced HT and renal damage in both IL-1Ra−/− and WT mice, suggesting suppression of IL-1 may provide an additional strategy to protect against renal damage in hypertensive patients.

scholarly journals Blocking of interleukin-1 suppresses both angiotensin II-induced renal inflammation and hypertension

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
T Niida ◽  
K Isoda ◽  
K Kitamura ◽  
Y Okabayashi ◽  
T Kadoguchi ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Renal Function ◽  
Angiotensin Ii ◽  
Renal Damage ◽  
Interleukin 1 ◽  
Funding Source ◽  
Ang Ii ◽  
Glomerular Injury ◽  
Renal Inflammation ◽  
Induced Hypertension

Abstract Background Clinical hypertension is associated with renal inflammation and elevated circulating levels of proinflammatory cytokines. IL-1 receptor antagonist (IL-1Ra) is one of the most important anti-inflammatory cytokines and plays a crucial role in inflammation. Inhibition of IL-1 may contribute to modulation of the Angiotensin II (AngII)-induced hypertension response. This study aimed to elucidate the effects of IL-1Ra and anti-IL-1beta antibody (01BSUR) on AngII-induced hypertension and renal inflammation. Methods and results To determine the contribution of IL-1Ra to AngII-induced renal inflammation, male wild-type (WT) and IL-1Ra-deficient (IL-1Ra−/−) mice were infused with AngII (1000ng/kg/min) using subcutaneous osmotic pumps for 14 days. We checked blood pressure, histological change, and several mRNA expressions 14 days after infusion. Fourteen days after infusion, systolic blood pressure (197±5 vs 169±9 mmHg, p<0.05) in IL-1Ra−/− mice significantly increased compared with WT mice. Furthermore, on day 14 of AngII infusion, plasma IL-6 was 5.9-fold higher in IL-1Ra−/− versus WT mice (p<0.001); renal preproendothelin-1 mRNA expression was also significantly higher in IL-1Ra−/− mice (p<0.05). To examine renal function, we analyzed 24-hour urinary protein excretion and serum levels of blood urea nitrogen, creatinine, and uric acid in IL-1Ra−/− and WT mice. On day 14 of Ang II infusion, all levels increased significantly in IL-1Ra−/− mice compared with WT mice, suggesting that IL-1Ra deficiency reduced renal function following Ang II infusion. In addition, renal histology revealed that glomerular injury (Figure upper panels: PAS staining) and tubulointerstitial fibrosis (Figure lower panels: Elastica Masson staining) increased significantly in Ang II-infused IL-1Ra−/− versus Ang II-infused WT mice. Finally, we administrated 01BSUR to both IL-1Ra−/− and WT mice, and 01BSUR treatment decreased AngII-induced hypertension (162±17 vs 204±6 mmHg, p<0.05) and renal damage (glomerular injury and fibrosis of the tubulointerstitial area) in both IL-1Ra−/− and WT mice compared with IgG2a treatment. These findings suggest that 01BSUR suppresses Ang II-induced inflammation and renal injury. Conclusions Inhibition of interleukin-1 by both endogenous IL-1Ra and exogenous 01BSUR decreased AngII-induced hypertension and renal damage in mice, suggesting suppression of IL-1 may provide an additional strategy to protect against renal damage in hypertensive patients. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): JSPS KAKENHI

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 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<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.

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.

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.

Abstract P129: Angiotensin II Does Not Directly Stimulate The TLR4-MD2-MyD88 Inflammatory Pathway

Hypertension ◽  
2020 ◽  
Vol 76 (Suppl_1) ◽  
Author(s):  
Charles C Okechukwu ◽  
Mark C Chappell
Keyword(s):  
Angiotensin Ii ◽  
Renal Injury ◽  
Dose Range ◽  
Current Evidence ◽  
Ang Ii ◽  
Pre Treatment ◽  
Reported Data ◽  
Free Media ◽  
Rat Proximal Tubule

Current evidence suggests that the deleterious actions of Angiotensin II (Ang II) reflect activation of both innate and adaptive inflammatory pathways. Indeed, recent studies find that Ang II stimulates the TLR-4 signaling cascade to promote cytokine release and renal injury by directly binding to the TLR4 accessory protein MD2 to induce TLR-4 dimerization and internalization that is independent of the AT 1 receptor (AT 1 R). Moreover, knockdown of TLR4 or MD2 attenuates renal injury and expression of pro-inflammatory cytokines in a chronic Ang II infusion model and in rat proximal tubule NRK-52e cells treated with Ang II. In the present study, we evaluated the proposed Ang II-TLR4-MD2 pathway in the NRK-52e cells regarding the stimulation of the chemokine MCP-1 (CCL2) and activation of the TLR4-MyD88 complex. NRK-52e cells, maintained in antibiotic-free media, were transferred to serum-free media prior to stimulation with the TLR4 agonists LPS and palmitate or Ang II for 24 hrs; reported data are the means ± SEM, n=4. The NRK-52e cells were sensitive to a low dose of LPS (1 ng/ml) stimulating CCL2 release 20-fold [Basal: 24.3 ± 1.0 pg/ml vs. 504 ± 30.4 pg/ml, p<0.001]. The LPS induced release of CCL2 was abolished by the specific TLR4 inhibitor Tak-242 [TAK: 23.9 ± 1.3 pg/ml] and was significantly reduced by the MD2 inhibitor L48H37 [135 ± 24.2 pg/ml]. Palmitate [100 μM] also stimulated CCL2 release [482 ± 21.0 pg/ml; p<0.001] that was abolished by TAK [32.3 ± 6.3 pg/ml]. The overall effects are consistent with previously reported responses to LPS and palmitate in these cells, as well as TLR4 protein expression and TAK inhibition. However, Ang II treatment over a dose range of 0.1 to 10 μM for 24 hrs failed to elicit CCL2 release [24.3 ± 1.0, 22.6 ± 0.5, and 27.6 ± 2.3 pg/ml, respectively; P>0.1 vs. Basal]. Ang II [1 μM] also failed to augment the CCL2 response to LPS [496 ± 6.5 pg/ml] or palmitate [511 ± 35.0 pg/ml]. Finally, pre-treatment of the NRK-52e cells with the AT 1 R antagonist candesartan [5 μM] failed to attenuate CCL2 release to LPS [512 ± 21 pg/ml]. We conclude that Ang II does not directly stimulate the TLR4-MD2 complex to induce CCL2 and that the inflammatory events associated with Ang II in vivo may reflect the release of other factors (LPS, AGEs, HMGB1) that serve as TLR-4 agonists.

Renoprotective effect of renal liver-type fatty acid binding protein and angiotensin II type 1a receptor loss in renal injury caused by RAS activation

2014 ◽  
Vol 306 (6) ◽  
pp. F655-F663 ◽  
Author(s):  
Daisuke Ichikawa ◽  
Atsuko Kamijo-Ikemori ◽  
Takeshi Sugaya ◽  
Yugo Shibagaki ◽  
Takashi Yasuda ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Angiotensin Ii ◽  
Renal Injury ◽  
Fatty Acid Binding Protein ◽  
Ang Ii ◽  
Fatty Acid Binding ◽  
Renoprotective Effect ◽  
Acid Binding Protein ◽  
Ras Activation ◽  
Tubulointerstitial Damage

The aim of this study was to assess the renoprotective effect of renal human liver-type fatty acid binding protein (hL-FABP) and angiotensin II (ANG II) type 1A receptor (AT1a) loss in renal injury caused by renin-angiotensin system (RAS) activation. We established hL-FABP chromosomal transgenic mice (L-FABP+/−AT1a+/+), crossed the L-FABP+/−AT1a+/+ with AT1a knockdown homo mice (L-FABP−/−AT1a−/−), and generated L-FABP+/−AT1a hetero mice (L-FABP+/−AT1a+/−). After the back-cross of these cubs, L-FABP+/−AT1a−/− were obtained. To activate the renal RAS, wild-type mice (L-FABP−/−AT1a+/+), L-FABP+/−AT1a+/+, L-FABP−/−AT1a+/−, L-FABP+/−AT1a+/−, L-FABP−/−AT1a−/−, and L-FABP+/−AT1a−/− were administered high-dose systemic ANG II infusion plus a high-salt diet for 28 days. In the L-FABP−/−AT1a+/+, RAS activation (L-FABP−/−AT1a+/+RAS) caused hypertension and tubulointerstitial damage. In the L-FABP+/−AT1a+/+RAS, tubulointerstitial damage was significantly attenuated compared with L-FABP−/−AT1a+/+RAS. In the AT1a partial knockout (AT1a+/−) or complete knockout (AT1a−/−) mice, reduction of AT1a expression led to a significantly lower degree of renal injury compared with L-FABP−/−AT1a+/+RAS or L-FABP+/−AT1a+/+RAS mice. Renal injury in L-FABP+/−AT1a+/−RAS mice was significantly attenuated compared with L-FABP−/−AT1a+/−RAS mice. In both L-FABP−/−AT1a−/−RAS and L-FABP+/−AT1a−/−RAS mice, renal damage was rarely found. The degrees of renal hL-FABP expression and urinary hL-FABP levels increased by RAS activation and gradually decreased along with reduction of AT1a expression levels. In conclusion, in this mouse model, renal hL-FABP expression and a decrease in AT1a expression attenuated tubulointerstitial damage due to RAS activation.

P0108RESOLVIN D2 TREATMENT AMELIARATES ANGIOTENSINII-INDUCED RENAL INJURY

2020 ◽  
Vol 35 (Supplement_3) ◽  
Author(s):  
Raquel Rodrigues-Díez ◽  
Lucía Serrano Díaz del Campo ◽  
Ana García Redonde ◽  
Mercedes Salaices ◽  
Ana Briones
Keyword(s):  
Experimental Model ◽  
Renal Injury ◽  
Interstitial Fibrosis ◽  
Ischemia Reperfusion ◽  
Lipid Mediators ◽  
Renal Diseases ◽  
Pcr Analysis ◽  
Type I ◽  
Ang Ii ◽  
Renal Inflammation

Abstract Background and Aims Renal inflammation is a protective response to several types of renal insults. Resolution is the ideal outcome of acute inflammation, however fail in resolution leads to chronic inflammation, progressive renal fibrosis and finally to end-stage renal failure. Recently is has been established that resolution of inflammation is mediated not only by disappearance of pro-inflammatory signals (including lipid mediators such as leukotrienes and prostaglandins) but also by activation of specialized pro-resolving mediators (SPM) including lipid mediators such as protectins (PD) and resolvins (Rvs) derived from omega-3 fatty acids precursors. Several authors have explored the role of different SPM in the treatment of experimental nephropathies. In the experimental model of bilateral ischemia/reperfusion pro-resolving mediators such as RvDs and PD1 were endogenously produced in the kidney in response to the injury. In this model, administration of RvD1 or PD1 before the ischemia or after the reperfusion showed a renoprotective effect. Moreover in the unilateral ureteral obstruction model RvE1 and RvD1administration inhibited interstitial fibrosis. One of the key mediators of renal injury is Angiotensin II (AngII) that participates in the pathogenesis of renal diseases through the regulation of two key processes, inflammation and fibrosis. Therefore, the aim of this study was to investigate the effect of the pro-resolving mediator Resolvin D2 (RvD2) in AngII-induced renal injury Method We used C57BL/6 mice that were infused with AngII (1440 µg/kg/day o 1000 ng/Kg/min). After 7 days of AngII treatment, when hypertension was already established, mice were treated with RvD2 (100ng/mouse ip) every two days for additional 7 days. At day 14 mice were sacrificed and kidneys were removed for protein and gene expression analysis and for histological examination. Results In our experimental model RvD2 ameliorated renal injury assessed by expression of NGAL both at mRNA and protein levels. In addition AngII-treated mice presented significant reduction in glomerular size that was increased by RvD2 treatment reaching values comparable to control. In addition, RvD2 inhibited the activation of inflammatory markers including COX-2, IL-6 and MCP-1 induced by AngII and reduced the number of F4/80+ infiltrated macrophages. We next evaluated the effect of RvD2 in the activation of NFκB, a key signaling pathway in inflammation. We observed that RvD2 inhibited AngII-induced NFkB activation. Moreover, RT-PCR analysis indicated that Ang II increased the expression of Tenascin C, a component of the fibrogenic niche in kidney fibrosis, as well as Type-I Collagen and Fibronectin and these levels were significantly reduced by the treatment with RvD2. These results were also confirmed by Masson-Goldner trichrome staining. Importantly, these effects were independent of changes in blood pressure. We finally studied whether the effects of RvD2 might be related to the modulation of RvDs endogenous biosynthesis pathway or RvD2 receptor GPR-18. mRNA analysis showed that AngII did not modified the expression levels of RvD2 biosynthesis enzymes including LOX-5 and LOX-15 nor GPR-18. However, RvD2 treatment increased the expression of LOX-15 and GPR-18 and downregulated LOX-5 indicating a possible auto-regulatory mechanism of RvD2 Conclusion Our results evidence a dual beneficial effect of the pro-resolvin mediator RvD2 in Ang II-induced renal injury as RvD2 treatment reversed not only renal inflammation but also tubulo-interstitial fibrosis. Hence, synthetic pro-resolving mediators would be an interesting therapeutic option for renal diseases.

Role of angiotensin II in experimental membranous nephropathy

1988 ◽  
Vol 254 (4) ◽  
pp. F500-F506
Author(s):  
F. B. Gabbai ◽  
C. B. Wilson ◽  
R. C. Blantz
Keyword(s):  
Angiotensin Ii ◽  
Hydrostatic Pressure ◽  
Membranous Nephropathy ◽  
Enzyme Inhibitor ◽  
Chronic Administration ◽  
Ang Ii ◽  
Glomerular Injury ◽  
Single Nephron ◽  
Glomerular Hemodynamics

Glomerular hemodynamics measurements in rats with experimental membranous nephropathy [passive Heymann nephritis (PHN)] have demonstrated that the appearance of proteinuria 5 days after administration of anti-Fx1A antibody is temporally related to changes in the glomerular ultrafiltration coefficient (LpA). Previous studies in other models of glomerular injury have suggested a significant role for angiotensin II (ANG II) in the glomerular hemodynamic abnormalities. To evaluate the possible role of ANG II in the LpA decrease, converting enzyme inhibitor (CEI) was administered acutely or chronically (5 days before and after induction of PHN) to rats with PHN. Acute ANG II blockade produced a fall in mean arterial pressure (MAP), single-nephron glomerular filtration rate (SNGFR), absolute proximal reabsorption (APR), single-nephron plasma flow, single-nephron blood flow, and glomerular capillary hydrostatic pressure (PG); however, no changes in LpA were detected. Chronic administration of CEI (MK421, 5 mg.kg-1.day-1) in the drinking water was associated with a fall in MAP; however, both SNGFR and APR increased. PG and the transcapillary hydrostatic pressure gradient were unchanged, and LpA remained depressed. These results suggest that reduction of LpA in rats with PHN is ANG II independent and that other mechanisms are required to explain these changes in glomerular hemodynamics.

scholarly journals Specific endothelial heparin-binding EGF-like growth factor deletion ameliorates renal injury induced by chronic angiotensin II infusion

2016 ◽  
Vol 311 (4) ◽  
pp. F695-F707 ◽  
Author(s):  
Fenghua Zeng ◽  
Lance A. Kloepfer ◽  
Charlene Finney ◽  
André Diedrich ◽  
Raymond C. Harris
Keyword(s):  
Angiotensin Ii ◽  
Renal Injury ◽  
Egf Receptor ◽  
Kidney Diseases ◽  
Ang Ii ◽  
Heparin Binding ◽  
Egfr Activation ◽  
Perivascular Area ◽  
Endothelial Integrity

Transactivation of EGF receptor (EGFR) by angiotensin II (Ang II) plays important roles in the initiation and progression of chronic kidney diseases. Studies suggest that heparin-binding EGF-like factor (HB-EGF) may be a critical mediator in this process, but its role in vivo has not been investigated. In the current study, we found that in response to Ang II infusion, kidneys from endothelial HB-EGF deletion mice had significantly reduced EGFR activation compared with controls. Meanwhile, deletion of endothelial HB-EGF expression decreased Ang II infusion related renal injury, as demonstrated by 1) less albuminuria; 2) less glomerulosclerosis; 3) preserved endothelial integrity and decreased podocyte injury, as shown by greater glomerular tuft area and WT1-positive cells, and fewer apoptotic cells measured by cleaved caspase 3 staining; 4) reduced inflammation in the perivascular area and interstitium measured by F4/80 and CD3 immunostaining; and 5) reduced renal fibrosis. In conclusion, our results suggest that shedding of HB-EGF from endothelium plays an important role in Ang II-induced renal injury by linking Ang II-AT1R with EGFR transactivation. Inhibition of HB-EGF shedding could be a potential therapeutic strategy for chronic kidney disease.

Sign in / Sign up

Export Citation Format

Share Document