Chronic inhibition of nuclear factor-κB attenuates renal injury in the 5/6 renal ablation model

2007 ◽  
Vol 292 (1) ◽  
pp. F92-F99 ◽  
Author(s):  
Clarice K. Fujihara ◽  
Gláucia R. Antunes ◽  
Ana L. Mattar ◽  
Denise M. A. C. Malheiros ◽  
José M. Vieira ◽  
...  
Keyword(s):  
Renal Injury ◽  
Immunohistochemical Analysis ◽  
Nuclear Factor Κb ◽  
Pyrrolidine Dithiocarbamate ◽  
Sham Operation ◽  
Ang Ii ◽  
Renal Ablation ◽  
Glomerular Hypertension ◽  
New Strategy ◽  
Ablation Model

Recent studies indicated that the nuclear transcription factor, NF-κB, activates a number of proinflammatory genes in subjects with progressive nephropathies. We investigated whether NF-κB inhibition limits progressive renal injury in the 5/6 renal ablation model (Nx). Adult male Munich-Wistar rats were subdivided in four groups: S ( n = 16), subjected to sham operation; S+PDTC ( n = 18), sham-operated rats receiving the NF-κB inhibitor pyrrolidine-dithiocarbamate (PDTC; 60 mg·kg−1·day−1) in drinking water; Nx ( n = 16), Nx rats receiving vehicle only; and Nx+PDTC ( n = 19), Nx rats given PDTC as above. Thirty days after renal ablation, Nx rats exhibited systemic and glomerular hypertension. Only the former was attenuated by PDTC treatment. Sixty days after renal ablation, Nx rats exhibited marked hypertension, albuminuria and creatinine retention, as well as glomerulosclerosis and cortical interstitial expansion/inflammation. Immunohistochemical analysis of Nx rats showed renal interstitial infiltration by macrophages and by cells staining positively for ANG II and its receptor, AT1. Glomerular and interstitial cells expressing the p65 subunit of the NF-κB system were also found. PDTC treatment attenuated renal injury and inflammation, as well as the density of cells staining positively for the p65 subunit. Activation of the NF-κB system plays an important role in the pathogenesis of renal injury in the Nx model. Inhibition of this system may represent a new strategy to prevent the progression of chronic kidney disease.

Renal expression of COX-2, ANG II, and AT1 receptor in remnant kidney: strong renoprotection by therapy with losartan and a nonsteroidal anti-inflammatory

2004 ◽  
Vol 286 (5) ◽  
pp. F945-F954 ◽  
Author(s):  
Anderson Ricardo Roman Gonçalves ◽  
Clarice Kazue Fujihara ◽  
Ana Lúcia Mattar ◽  
Denise Maria Avancini Costa Malheiros ◽  
I. L. Noronha ◽  
...  
Keyword(s):  
Renal Injury ◽  
Sham Operation ◽  
Ang Ii ◽  
Treatment Groups ◽  
Renal Structure ◽  
Renal Ablation ◽  
Cox 2 ◽  
Anti Inflammatory ◽  
Antiinflammatory Effects ◽  
Structural Injury

Chronic renal injury can be mediated by angiotensin II (ANG II) and prostanoids through hemodynamic and inflammatory mechanisms and attenuated by individual suppression of these mediators. In rats with ⅚ renal ablation (Nx), we investigated 1) the intrarenal distribution of COX-2, ANG II, and the AT1 receptor (AT1R); 2) the renoprotective and antiinflammatory effects of an association between the AT1R blocker, losartan (Los), and the gastric sparing anti-inflammatory nitroflurbiprofen (NOF). Adult male Munich-Wistar rats underwent Nx or sham operation (S), remaining untreated for 30 days, after which renal structure was examined in 12 Nx rats (Nxpre). The remaining rats were followed during an additional 90 days, distributed among 4 treatment groups: NxV (vehicle), NxLos (Los), NxNOF (NOF), and NxLos/NOF (Los/NOF). Nxpre rats exhibited marked albuminuria, hypertension, glomerulosclerosis, interstitial expansion, and macrophage infiltration, accompanied by abnormal glomerular, vascular, and interstitial COX-2 expression. ANG II appeared in interstitial cells, in contrast to S, in which ANG II was virtually confined to afferent arterioles. Intrarenal AT1R distribution shifted from mostly tubular in S to predominantly interstitial in Nxpre. All these changes were aggravated at 120 days and attenuated by Los and NOF monotherapies. Los/NOF treatment arrested renal structural injury and ANG II expression and reversed hypertension, albuminuria, and renal inflammation. In conclusion, abnormal expression of COX-2, ANG II, and AT1R may be key to development of renal injury in Nx. Concomitant COX-2 inhibition and AT1R blockade arrested renal injury and may represent a useful strategy in the treatment of chronic nephropathies.

scholarly journals Curcumin Induces Nrf2 Nuclear Translocation and Prevents Glomerular Hypertension, Hyperfiltration, Oxidant Stress, and the Decrease in Antioxidant Enzymes in 5/6 Nephrectomized Rats

2012 ◽  
Vol 2012 ◽  
pp. 1-14 ◽  
Author(s):  
Edilia Tapia ◽  
Virgilia Soto ◽  
Karla Mariana Ortiz-Vega ◽  
Guillermo Zarco-Márquez ◽  
Eduardo Molina-Jijón ◽  
...  
Keyword(s):  
Antioxidant Enzymes ◽  
Protective Effect ◽  
Renal Injury ◽  
Nuclear Translocation ◽  
Interstitial Fibrosis ◽  
Oxidant Stress ◽  
Systemic Hypertension ◽  
Glomerular Sclerosis ◽  
Renal Ablation ◽  
Glomerular Hypertension

Renal injury resulting from renal ablation induced by 5/6 nephrectomy (5/6NX) is associated with oxidant stress, glomerular hypertension, hyperfiltration, and impaired Nrf2-Keap1 pathway. The purpose of this work was to know if the bifunctional antioxidant curcumin may induce nuclear translocation of Nrf2 and prevents 5/6NX-induced oxidant stress, renal injury, decrease in antioxidant enzymes, and glomerular hypertension and hyperfiltration. Four groups of rats were studied: (1) control, (2) 5/6NX, (3) 5/6NX+CUR,and (4) CUR (n=8–10). Curcumin was given by gavage to NX5/6+CURand CUR groups (60 mg/kg/day) starting seven days before surgery. Rats were studied 30 days after NX5/6 or sham surgery. Curcumin attenuated 5/6NX-induced proteinuria, systemic and glomerular hypertension, hyperfiltration, glomerular sclerosis, interstitial fibrosis, interstitial inflammation, and increase in plasma creatinine and blood urea nitrogen. This protective effect was associated with enhanced nuclear translocation of Nrf2 and with prevention of 5/6NX-induced oxidant stress and decrease in the activity of antioxidant enzymes. It is concluded that the protective effect of curcumin against 5/6NX-induced glomerular and systemic hypertension, hyperfiltration, renal dysfunction, and renal injury was associated with the nuclear translocation of Nrf2 and the prevention of both oxidant stress and the decrease of antioxidant enzymes.

Angiotensin II control of the renal microcirculation in rats with reduced renal mass

1990 ◽  
Vol 258 (2) ◽  
pp. F414-F422 ◽  
Author(s):  
J. C. Pelayo ◽  
A. H. Quan ◽  
P. F. Shanley
Keyword(s):  
Renal Failure ◽  
Angiotensin Ii ◽  
Renal Mass ◽  
Wistar Rats ◽  
Sham Group ◽  
Ang Ii ◽  
Renal Ablation ◽  
Glomerular Hypertension ◽  
Single Nephron ◽  
Glomerular Ultrafiltration

It has been suggested that angiotensin II (ANG II) activation after renal ablation contributes to the altered glomerular dynamics and proteinuria that characterizes this model of chronic renal failure. In the present study, male Munich-Wistar rats underwent 75% renal ablation (Nx group). Two weeks later, micropuncture studies were performed in sham-operated rats (sham group) and Nx group rats during intravenous infusion of either a vehicle or two ANG II inhibitors, namely [Sar1, Ala8]ANG II or MK-421 administered at a rate of 0.3 and 1 mg.kg body wt-1.h-1, respectively. Acute ANG II inhibition in sham group had no effect on mean arterial pressure (MAP), glomerular dynamics, or proteinuria. In contrast, in Nx group ANG II inhibition lessened glomerular hypertension (from 64.7 +/- 1.0 to 55.4 +/- 1.7 mmHg, P less than 0.0001) the result of postglomerular vasodilation (P less than 0.01), normalized the glomerular ultrafiltration coefficient (from 0.038 +/- 0.002 to 0.005 +/- 0.002 nl.s-1.mmHg-1, P less than 0.0001), and attenuated proteinuria (from 42.1 +/- 6.5 to 28.1 +/- 5.4 micrograms/min, P less than 0.01). MAP, single-nephron GFR and plasma flow were unaffected. These results suggest that ANG II activity is enhanced in nephrectomy, contributing in a major way to altered glomerular dynamics and proteinuria.

scholarly journals Innate And Adaptive Immunity are Progressively Activated in Parallel with Renal Injury in the 5/6 Renal Ablation Model

2017 ◽  
Vol 7 (1) ◽  
Author(s):  
Camilla Fanelli ◽  
Simone C. A. Arias ◽  
Flavia G. Machado ◽  
Jessica K. Okuma ◽  
Denise M. A. C. Malheiros ◽  
...  
Keyword(s):  
Adaptive Immunity ◽  
Renal Injury ◽  
Innate And Adaptive Immunity ◽  
Renal Ablation ◽  
Ablation Model

Losartan-hydrochlorothiazide association promotes lasting blood pressure normalization and completely arrests long-term renal injury in the 5/6 ablation model

2007 ◽  
Vol 292 (6) ◽  
pp. F1810-F1818 ◽  
Author(s):  
Clarice Kazue Fujihara ◽  
Denise M. A. C. Malheiros ◽  
Roberto Zatz
Keyword(s):  
Blood Pressure ◽  
Drinking Water ◽  
Adult Male ◽  
Renal Injury ◽  
Wistar Rats ◽  
Long Period ◽  
Morphological Studies ◽  
Renal Ablation ◽  
Ablation Model

The possible long-term renoprotective effects of treatment with thiazides, either as monotherapy or associated with renin-angiotensin suppressors, have not been assessed. We investigated the effect of hydrochlorothiazide (H), alone or combined with losartan (L), in the 5/6 renal ablation model (Nx). Adult male Munich-Wistar rats underwent Nx, remaining untreated for 1 mo. At this time, functional and morphological studies were performed in 21 rats (group Nxpre). The remaining rats were distributed among groups: Nx, no treatment; Nx+L, receiving L, 50 mg·kg−1·day−1 in the drinking water; Nx+H, receiving H, 6 mg·kg−1·day−1 in drinking water; and Nx+L+H, receiving both L and H as described. At 30 days of treatment, systemic and glomerular pressures were markedly elevated in group Nx. Both H and L attenuated hypertension, whereas combined L+H treatment completely normalized both pressures. Eight months after Nx, mortality approached 70% in untreated rats, whereas severe albuminuria, hypertension, glomerulosclerosis, and interstitial expansion were observed. H and L attenuated, but did not prevent, mortality, hypertension, and renal injury. Combined L+H treatment completely prevented mortality, normalized albuminuria and blood pressure, and arrested renal injury at levels found 1 mo after ablation, despite the unusually long period of observation. Combined L+H treatment may represent an effective therapeutic alternative to prevent progression of chronic nephropathies.

scholarly journals Cigarette smoke condensate aggravates renal injury in the renal ablation model

2002 ◽  
Vol 61 (6) ◽  
pp. 2090-2098 ◽  
Author(s):  
Giulio Odoni ◽  
Hiroaki Ogata ◽  
Christiane Viedt ◽  
Kerstin Amann ◽  
Eberhard Ritz ◽  
...  
Keyword(s):  
Cigarette Smoke ◽  
Renal Injury ◽  
Cigarette Smoke Condensate ◽  
Renal Ablation ◽  
Ablation Model

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.

Gene expression reveals vulnerability to oxidative stress and interstitial fibrosis of renal outer medulla to nonhypertensive elevations of ANG II

2003 ◽  
Vol 284 (5) ◽  
pp. R1219-R1230 ◽  
Author(s):  
Baozhi Yuan ◽  
Mingyu Liang ◽  
Zhizhang Yang ◽  
Elizabeth Rute ◽  
Norman Taylor ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Western Blot ◽  
Renal Injury ◽  
Interstitial Fibrosis ◽  
Control Period ◽  
Renal Medulla ◽  
Differentially Expressed ◽  
Ang Ii ◽  
Outer Medulla ◽  
Renal Outer Medulla

The present study was designed to determine whether nonhypertensive elevations of plasma ANG II would modify the expression of genes involved in renal injury that could influence oxidative stress and extracellular matrix formation in the renal medulla using microarray, Northern, and Western blot techniques. Sprague-Dawley rats were infused intravenously with either ANG II (5 ng · kg−1 · min−1) or vehicle for 7 days ( n = 6/group). Mean arterial pressure averaged 110 ± 0.6 mmHg during the control period and 113 ± 0.4 mmHg after ANG II. The mRNA of 1,751 genes (∼80% of all currently known rat genes) that was differentially expressed (ANG II vs. saline) in renal outer and inner medulla was determined. The results of 12 hybridizations indicated that in response to ANG II, 11 genes were upregulated and 25 were downregulated in the outer medulla, while 11 were upregulated and 13 were downregulated in the inner medulla. These differentially expressed genes, most of which were not known previously to be affected by ANG II in the renal medulla, were found to group into eight physiological pathways known to influence renal injury and kidney function. Particularly, expression of several genes would be expected to increase oxidative stress and interstitial fibrosis in the outer medulla. Western blot analyses confirmed increased expression of transforming growth factor-β1 and collagen type IV proteins in the outer medulla. Results demonstrate that nonhypertensive elevations of plasma ANG II can significantly alter the expression of a variety of genes in the renal outer medulla and suggested the vulnerability of the renal outer medulla to the injurious effect of ANG II.

scholarly journals Immunoglobulin light chains activate nuclear factor-κB in renal epithelial cells through a Src-dependent mechanism

Blood ◽  
2011 ◽  
Vol 117 (4) ◽  
pp. 1301-1307 ◽  
Author(s):  
Wei-Zhong Ying ◽  
Pei-Xuan Wang ◽  
Kristal J. Aaron ◽  
Kolitha Basnayake ◽  
Paul W. Sanders
Keyword(s):  
Epithelial Cells ◽  
Tyrosine Phosphorylation ◽  
Renal Injury ◽  
Src Kinase ◽  
Nuclear Factor Κb ◽  
Light Chains ◽  
Nuclear Factor ◽  
Monocyte Chemoattractant Protein 1 ◽  
Renal Epithelial Cells ◽  
Iκb Kinase

Abstract One of the major attendant complications of multiple myeloma is renal injury, which contributes significantly to morbidity and mortality in this disease. Monoclonal immunoglobulin free light chains (FLCs) are usually directly involved, and tubulointerstitial renal injury and fibrosis are prominent histologic features observed in myeloma. The present study examined the role of monoclonal FLCs in altering the nuclear factor κ light chain enhancer of activated B cells (NF-κB) activity of renal epithelial cells. Human proximal tubule epithelial cells exposed to 3 different human monoclonal FLCs demonstrated Src kinase–dependent activation of the NF-κB pathway, which increased production of monocyte chemoattractant protein-1 (MCP-1). Tyrosine phosphorylation of inhibitor of κB kinases (IKKs) IKKα and IKKβ and a concomitant increase in inhibitor of κB (IκB) kinase activity in cell lysates were observed. Time-dependent, Src kinase–dependent increases in serine and tyrosine phosphorylation of IκBα and NF-κB activity were also demonstrated. Proteasome inhibition partially blocked FLC-induced MCP-1 production. These findings fit into a paradigm characterized by FLC-induced redox-signaling events that activated the canonical and atypical (IKK-independent) NF-κB pathways to promote a proinflammatory, profibrotic renal environment.

Attenuation of lung reperfusion injury after transplantation using an inhibitor of nuclear factor-κB

2000 ◽  
Vol 279 (3) ◽  
pp. L528-L536 ◽  
Author(s):  
Scott D. Ross ◽  
Irving L. Kron ◽  
James J. Gangemi ◽  
Kimberly S. Shockey ◽  
Mark Stoler ◽  
...  
Keyword(s):  
Lung Function ◽  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Graft Function ◽  
Nuclear Factor Κb ◽  
Pyrrolidine Dithiocarbamate ◽  
Nuclear Factor ◽  
Mean Pulmonary Arterial Pressure ◽  
Pulmonary Arterial

A central role for nuclear factor-κB (NF-κB) in the induction of lung inflammatory injury is emerging. We hypothesized that NF-κB is a critical early regulator of the inflammatory response in lung ischemia-reperfusion injury, and inhibition of NF-κB activation reduces this injury and improves pulmonary graft function. With use of a porcine transplantation model, left lungs were harvested and stored in cold Euro-Collins preservation solution for 6 h before transplantation. Activation of NF-κB occurred 30 min and 1 h after transplant and declined to near baseline levels after 4 h. Pyrrolidine dithiocarbamate (PDTC), a potent inhibitor of NF-κB, given to the lung graft during organ preservation (40 mmol/l) effectively inhibited NF-κB activation and significantly improved lung function. Compared with control lungs 4 h after transplant, PDTC-treated lungs displayed significantly higher oxygenation, lower Pco2, reduced mean pulmonary arterial pressure, and reduced edema and cellular infiltration. These results demonstrate that NF-κB is rapidly activated and is associated with poor pulmonary graft function in transplant reperfusion injury, and targeting of NF-κB may be a promising therapy to reduce this injury and improve lung function.

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