NF-κB blockade during short-term l-NAME and salt overload strongly attenuates the late development of chronic kidney disease

2020 ◽  
Vol 319 (2) ◽  
pp. F215-F228
Author(s):  
Karin Carneiro Oliveira ◽  
Fernanda Florencia Fregnan Zambom ◽  
Amanda Helen Albino ◽  
Simone Costa Alarcon Arias ◽  
Victor Ferreira Ávila ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Innate Immunity ◽  
Kidney Disease ◽  
Renal Injury ◽  
Pyrrolidine Dithiocarbamate ◽  
Low Grade ◽  
Glomerular Injury ◽  
High Salt Diet ◽  
Renal Inflammation ◽  
Oxide Synthase

Nitric oxide synthase inhibition by Nω-nitro-l-arginine methyl ester (l-NAME) plus a high-salt diet (HS) is a model of chronic kidney disease (CKD) characterized by marked hypertension and renal injury. With cessation of treatment, most of these changes subside, but progressive renal injury develops, associated with persistent low-grade renal inflammation. We investigated whether innate immunity, and in particular the NF-κB system, is involved in this process. Male Munich-Wistar rats received HS + l-NAME (32 mg·kg−1·day−1), whereas control rats received HS only. Treatment was ceased after week 4 when 30 rats were studied. Additional rats were studied at week 8 ( n = 30) and week 28 ( n = 30). As expected, HS + l-NAME promoted severe hypertension, albuminuria, and renal injury after 4 wk of treatment, whereas innate immunity activation was evident. After discontinuation of treatments, partial regression of renal injury and inflammation occurred, along with persistence of innate immunity activation at week 8. At week 28, glomerular injury worsened, while renal inflammation persisted and renal innate immunity remained activated. Temporary administration of the NF-κB inhibitor pyrrolidine dithiocarbamate, in concomitancy with the early 4-wk HS + l-NAME treatment, prevented the development of late renal injury and inflammation, an effect that lasted until the end of the study. Early activation of innate immunity may be crucial to the initiation of renal injury in the HS + l-NAME model and to the autonomous progression of chronic nephropathy even after cessation of the original insult. This behavior may be common to other conditions leading to CKD.

Triiodothyronine attenuates the progression of renal injury in a rat model of chronic kidney disease

2018 ◽  
Vol 96 (6) ◽  
pp. 603-610 ◽  
Author(s):  
Sahar M. El Agaty
Keyword(s):  
Nitric Oxide ◽  
Chronic Kidney Disease ◽  
Nitric Oxide Synthase ◽  
Kidney Disease ◽  
Renal Injury ◽  
Serum Levels ◽  
Female Rats ◽  
Renal Tubules ◽  
Oxide Synthase ◽  
Remnant Kidney

This study was designed to investigate whether and how triiodothyronine (T3) affects renal function in an experimental model of chronic kidney disease. Twenty-four female rats were divided into the following groups: sham-operated control group (n = 8), 5/6 nephrectomized group (Nx, n = 8), and 5/6 nephrectomized group treated with T3 for 2 weeks (T3-Nx, n = 8). T3 administration significantly decreased serum levels of urea, creatinine, tumour necrosis factorα, and interleukin-6 compared with serum levels in the Nx group. The levels of malondialdehyde, transforming growth factor β, fibronectin, and collagen IV, as well as the expression of inducible nitric oxide synthase, nuclear factor κB, poly(ADP-ribose) polymerase, caspase-3, and Bax were all significantly decreased, though not normalized, in the remnant kidney of rats in the T3-Nx group compared with Nx rats. Glutathione, heme oxygenase-1 levels, as well as endothelial nitric oxide synthase expression were increased in the remnant kidney of the T3-Nx group. Histological studies revealed focal necrosis of renal tubules associated with inflammatory cell infiltration and fibrosis in the Nx group. These changes were alleviated in T3-Nx rats. This study showed that T3 administration attenuated the clinical and histological signs of renal injury in 5/6 nephrectomized rats by mitigating renal oxidative stress, inflammation, apoptosis, and fibrosis.

scholarly journals Nicorandil, a Katp channel opener, alleviates chronic renal injury by targeting podocytes and macrophages

2012 ◽  
Vol 303 (3) ◽  
pp. F339-F349 ◽  
Author(s):  
Yoshifuru Tamura ◽  
Katsuyuki Tanabe ◽  
Wataru Kitagawa ◽  
Shunya Uchida ◽  
George F. Schreiner ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Xanthine Oxidase ◽  
Renal Injury ◽  
Vascular System ◽  
K Channel ◽  
Sulfonylurea Receptor ◽  
Glomerular Injury ◽  
Tubulointerstitial Injury

Nicorandil exhibits a protective effect in the vascular system, which is thought to be due to vasodilatation from opening ATP-dependent potassium channels and donation of nitric oxide. Recently, nicorandil was shown to be renoprotective in models of acute kidney injury and glomerulonephritis. However, the specific mechanisms of renoprotection are unclear. We evaluated the effect of nicorandil on the rat remnant kidney model of chronic kidney disease. Blood pressure was unchanged by a 10-wk course of nicorandil, while albuminuria was significantly reduced. Glomerular injury and tubulointerstitial injury were also ameliorated by nicorandil. Oxidative stress, as noted by renal nitrotyrosine level and urine 8-hydroxy-2′-deoxyguanosine, were elevated in this model and was significantly reduced by nicorandil treatment. Treatment was associated with maintenance of the mitochondrial antioxidant, manganese SOD, in podocytes and with suppression of xanthine oxidase expression in infiltrating macrophages. Interestingly, these two cell types express sulfonylurea receptor 2 (SUR2), a binding site of nicorandil in the ATP-dependent K channel. Consistently, we found that stimulating SUR2 with nicorandil prevented angiotensin II-mediated upregulation of xanthine oxidase in the cultured macrophage, while xanthine oxidase expression was rather induced by blocking SUR2 with glibenclamide. In conclusion, nicorandil reduces albuminuria and ameliorates renal injury by blocking oxidative stress in chronic kidney disease.

scholarly journals Chronic exposure to hypoxia attenuates renal injury and innate immunity activation in the remnant kidney model

2019 ◽  
Vol 317 (5) ◽  
pp. F1285-F1292 ◽  
Author(s):  
Lisienny Campoli Tono Rempel ◽  
Viviane Dias Faustino ◽  
Orestes Foresto-Neto ◽  
Camilla Fanelli ◽  
Simone Costa Alarcon Arias ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Chronic Kidney Disease ◽  
Innate Immunity ◽  
Kidney Disease ◽  
Renal Injury ◽  
Cortical Area ◽  
Prolonged Exposure ◽  
Capillary Density ◽  
Renal Tissue ◽  
Peritubular Capillary

Hypoxia is thought to influence the pathogenesis of chronic kidney disease, but direct evidence that prolonged exposure to tissue hypoxia initiates or aggravates chronic kidney disease is lacking. We tested this hypothesis by chronically exposing normal rats and rats with 5/6 nephrectomy (Nx) to hypoxia. In addition, we investigated whether such effect of hypoxia would involve activation of innate immunity. Adult male Munich-Wistar rats underwent Nx ( n = 54) or sham surgery (sham; n = 52). Twenty-six sham rats and 26 Nx rats remained in normoxia, whereas 26 sham rats and 28 Nx rats were kept in a normobaric hypoxia chamber (12% O2) for 8 wk. Hypoxia was confirmed by immunohistochemistry for pimonidazole. Hypoxia was confined to the medullary area in sham + normoxia rats and spread to the cortical area in sham + hypoxia rats, without changing the peritubular capillary density. Exposure to hypoxia promoted no renal injury or elevation of the content of IL-1β or Toll-like receptor 4 in sham rats. In Nx, hypoxia also extended to the cortical area without ameliorating the peritubular capillary rarefaction but, unexpectedly, attenuated hypertension, inflammation, innate immunity activation, renal injury, and oxidative stress. The present study, in disagreement with current concepts, shows evidence that hypoxia exerts a renoprotective effect in the Nx model instead of acting as a factor of renal injury. The mechanisms for this unexpected beneficial effect are unclear and may involve NF-κB inhibition, amelioration of oxidative stress, and limitation of angiotensin II production by the renal tissue.

Pathogenic role of innate immunity in a model of chronic NO inhibition associated with salt overload

2019 ◽  
Vol 317 (4) ◽  
pp. F1058-F1067 ◽  
Author(s):  
Fernanda Florencia Fregnan Zambom ◽  
Karin Carneiro Oliveira ◽  
Orestes Foresto-Neto ◽  
Viviane Dias Faustino ◽  
Victor Ferreira Ávila ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Innate Immunity ◽  
Uric Acid ◽  
Renal Injury ◽  
Interstitial Fibrosis ◽  
Experimental Models ◽  
Pyrrolidine Dithiocarbamate ◽  
Glomerular Injury ◽  
Nitric Oxide Inhibition ◽  
Oxide Inhibition

Nitric oxide inhibition with Nω-nitro-l-arginine methyl ester (l-NAME), along with salt overload, leads to hypertension, albuminuria, glomerulosclerosis, glomerular ischemia, and interstitial fibrosis, characterizing a chronic kidney disease (CKD) model. Previous findings of this laboratory and elsewhere have suggested that activation of at least two pathways of innate immunity, Toll-like receptor 4 (TLR4)/NF-κB and nucleotide-binding oligomerization domain, leucine-rich repeat, and pyrin domain containing 3 (NLRP3) inflammasome/IL-1β, occurs in several experimental models of CKD and that progression of renal injury can be slowed with inhibition of these pathways. In the present study, we investigated whether activation of innate immunity, through either the TLR4/NF-κB or NLRP3/IL-1β pathway, is involved in the pathogenesis of renal injury in chronic nitric oxide inhibition with the salt-overload model. Adult male Munich-Wistar rats that received l-NAME in drinking water with salt overload (HS + N group) were treated with allopurinol (ALLO) as an NLRP3 inhibitor (HS + N + ALLO group) or pyrrolidine dithiocarbamate (PDTC) as an NF-κB inhibitor (HS + N + PDTC group). After 4 wk, HS + N rats developed hypertension, albuminuria, and renal injury along with renal inflammation, oxidative stress, and activation of both the NLRP3/IL-1β and TLR4/NF-κB pathways. ALLO lowered renal uric acid and inhibited the NLRP3 pathway. These effects were associated with amelioration of hypertension, albuminuria, and interstitial inflammation/fibrosis but not glomerular injury. PDTC inhibited the renal NF-κB system and lowered the number of interstitial cells staining positively for NLRP3. PDTC also reduced renal xanthine oxidase activity and uric acid. Overall, PDTC promoted a more efficient anti-inflammatory and nephroprotective effect than ALLO. The NLRP3/IL-1β and TLR4/NF-κB pathways act in parallel to promote renal injury/inflammation and must be simultaneously inhibited for best nephroprotection.

scholarly journals NLRP3 Deficiency Attenuates Renal Fibrosis and Ameliorates Mitochondrial Dysfunction in a Mouse Unilateral Ureteral Obstruction Model of Chronic Kidney Disease

2017 ◽  
Vol 2017 ◽  
pp. 1-10 ◽  
Author(s):  
Honglei Guo ◽  
Xiao Bi ◽  
Ping Zhou ◽  
Shijian Zhu ◽  
Wei Ding
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Mitochondrial Dysfunction ◽  
Ureteral Obstruction ◽  
Renal Fibrosis ◽  
Unilateral Ureteral Obstruction ◽  
Tubulointerstitial Fibrosis ◽  
Mitochondrial Morphology ◽  
Glomerular Injury ◽  
Matrix Deposition

Background and Aims. The nucleotide-binding domain and leucine-rich repeat containing PYD-3 (NLRP3) inflammasome has been implicated in the pathogenesis of chronic kidney disease (CKD); however, its exact role in glomerular injury and tubulointerstitial fibrosis is still undefined. The present study was performed to identify the function of NLRP3 in modulating renal injury and fibrosis and the potential involvement of mitochondrial dysfunction in the murine unilateral ureteral obstruction (UUO) model of CKD. Methods. Employing wild-type (WT) and NLRP3−/− mice with or without UUO, we evaluated renal structure, tissue injury, and mitochondrial ultrastructure, as well as expression of some vital molecules involved in the progression of fibrosis, apoptosis, inflammation, and mitochondrial dysfunction. Results. The severe glomerular injury and tubulointerstitial fibrosis induced in WT mice by UUO was markedly attenuated in NLRP3−/− mice as evidenced by blockade of extracellular matrix deposition, decreased cell apoptosis, and phenotypic alterations. Moreover, NLRP3 deletion reversed UUO-induced impairment of mitochondrial morphology and function. Conclusions. NLRP3 deletion ameliorates mitochondrial dysfunction and alleviates renal fibrosis in a murine UUO model of CKD.

Abstract 109: Gamma-adducin Effects on Microvascular Function- a Common Link of Hypertension Induced Chronic Kidney Disease and Cognitive Impairments

Hypertension ◽  
2017 ◽  
Vol 70 (suppl_1) ◽  
Author(s):  
Fan Fan ◽  
Shaoxun Wang ◽  
Paige N Mims ◽  
Chao Zhang ◽  
Richard J Roman
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Genetic Model ◽  
Cognitive Impairments ◽  
Microvascular Dysfunction ◽  
Small Region ◽  
Glomerular Injury ◽  
Flow Pressure ◽  
Underlying Mechanisms ◽  
Stop Flow

Chronic kidney disease (CKD) and cognitive impairments are common complications of hypertension. Increasing evidence suggests that the cognitive impairments associated with CKD may be related to microvascular dysfunction, however, the underlying mechanisms remain to be elucidated. FHH is a genetic model of hypertension-induced nephropathy. We found that the myogenic response and autoregulation of the renal and cerebral circulation is impaired in FHH rats, and was restored in a FHH.1 BN congenic strain in which a small region of Chr. 1 containing 15 genes, including Add3, from BN rats was transferred into the FHH background. The present study examined whether Add3 contributes to hypertension related CKD, and is associated with the development of cognitive impairments due to microvascular dysfunction. FHH rats exhibited impaired autoregulation of RBF in comparison with FHH.1 BN rats. Pgc estimated from the stop flow pressure increased by 20 mmHg in FHH rats when RPP was increased from 100 to 140 mmHg versus only 4 mmHg in FHH.1 BN . FHH rats developed severe renal injury, and proteinuria rose from 37 ± 2 to 260 ± 32 mg/day as they aged from 12 to 21 weeks, but rose by a significant lesser extent in FHH.1 BN and FHH.Add3 rats. Glomerular injury scores were 3.31 ± 0.01, 2.54 ± 0.01 and 2.50 ± 0.03, and areas of fibrosis in renal cortex were 23.57 ± 1.04%, 8.28 ± 0.33 and 4.71 ± 0.3 in DOCA/salt induced hypertensive FHH, FHH.1 BN and FHH.Add3 rats, respectively. CBF rose by 99 ± 7%, 64 ± 5% and 42 ± 4% in FHH, FHH.1 BN and FHH.Add3 rats, respectively, when MAP was increased from 100 to 190 mmHg, demonstrating impaired autoregulation of CBF in FHH rats was partially rescued with the replacement of wildtype Add3. BBB leakage was greater in FHH rats than in FHH.1 BN and FHH.Add3 rats, and hypertensive FHH rats exhibited marked neurodegeneration and vascular remodeling of the neocortex and hippocampus. The hypertensive FHH rats took 2.5 times longer time to escape from an eight-arm water maze in comparison to FHH.1 BN rats suggesting cognitive deficit. These results indicate that Add3 may play a role in the development of hypertension related CKD and cognitive impairments in FHH rats associated with microvascular dysfunction.

AT1 blockade during lactation as a model of chronic nephropathy: mechanisms of renal injury

2008 ◽  
Vol 294 (6) ◽  
pp. F1345-F1353 ◽  
Author(s):  
Flavia Gomes Machado ◽  
Elizabete Pereira Barros Poppi ◽  
Camilla Fanelli ◽  
Denise Maria Avancini Costa Malheiros ◽  
Roberto Zatz ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Renal Injury ◽  
Time Course ◽  
Structural Changes ◽  
Adult Life ◽  
Renin Angiotensin System ◽  
Urine Osmolality ◽  
Systemic Hypertension ◽  
Advanced Stages

Suppression of the renin-angiotensin system during lactation causes irreversible renal structural changes. In this study we investigated 1) the time course and the mechanisms underlying the chronic kidney disease caused by administration of the AT1 receptor blocker losartan during lactation, and 2) whether this untoward effect can be used to engender a new model of chronic kidney disease. Male Munich-Wistar pups were divided into two groups: C, whose mothers were untreated, and LLact, whose mothers received oral losartan (250 mg·kg−1·day−1) during the first 20 days after delivery. At 3 mo of life, both nephron number and the glomerular filtration rate were reduced in LLact rats, whereas glomerular pressure was elevated. Unselective proteinuria and decreased expression of the zonula occludens-1 protein were also observed, along with modest glomerulosclerosis, significant interstitial expansion and inflammation, and wide glomerular volume variation, with a stable subpopulation of exceedingly small glomeruli. In addition, the urine osmolality was persistently lower in LLact rats. At 10 mo of age, LLact rats exhibited systemic hypertension, heavy albuminuria, substantial glomerulosclerosis, severe renal interstitial expansion and inflammation, and creatinine retention. Conclusions are that 1) oral losartan during lactation can be used as a simple and easily reproducible model of chronic kidney disease in adult life, associated with low mortality and no arterial hypertension until advanced stages; and 2) the mechanisms involved in the progression of renal injury in this model include glomerular hypertension, glomerular hypertrophy, podocyte injury, and interstitial inflammation.

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