scholarly journals Effect of Angiotensin II and Small GTPase Ras Signaling Pathway Inhibition on Early Renal Changes in a Murine Model of Obstructive Nephropathy

2014 ◽  
Vol 2014 ◽  
pp. 1-14 ◽  
Author(s):  
Ana B. Rodríguez-Peña ◽  
Isabel Fuentes-Calvo ◽  
Neil G. Docherty ◽  
Miguel Arévalo ◽  
María T. Grande ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Angiotensin Ii ◽  
Kidney Disease ◽  
Akt Signaling ◽  
Small Gtpase ◽  
Tubulointerstitial Fibrosis ◽  
Ras Signaling ◽  
Signaling System ◽  
Ras Activation ◽  
Renal Tubulointerstitial Fibrosis

Tubulointerstitial fibrosis is a major feature of chronic kidney disease. Unilateral ureteral obstruction (UUO) in rodents leads to the development of renal tubulointerstitial fibrosis consistent with histopathological changes observed in advanced chronic kidney disease in humans. The purpose of this study was to assess the effect of inhibiting angiotensin II receptors or Ras activation on early renal fibrotic changes induced by UUO. Animals either received angiotensin II or underwent UUO. UUO animals received either losartan, atorvastatin, and farnesyl transferase inhibitor (FTI) L-744,832, or chaetomellic acid A (ChA). Levels of activated Ras, phospho-ERK1/2, phospho-Akt, fibronectin, andα-smooth muscle actin were subsequently quantified in renal tissue by ELISA, Western blot, and/or immunohistochemistry. Our results demonstrate that administration of angiotensin II induces activation of the small GTPase Ras/Erk/Akt signaling system, suggesting an involvement of angiotensin II in the early obstruction-induced activation of renal Ras. Furthermore, upstream inhibition of Ras signalling by blocking either angiotensin AT1 type receptor or by inhibiting Ras prenylation (atorvastatin, FTI o ChA) reduced the activation of the Ras/Erk/Akt signaling system and decreased the early fibrotic response in the obstructed kidney. This study points out that pharmacological inhibition of Ras activation may hold promise as a future strategy in the prevention of renal fibrosis.

scholarly journals Reduced Expression of Metallothionein-I/II in Renal Proximal Tubules Is Associated with Advanced Chronic Kidney Disease

Toxins ◽  
2021 ◽  
Vol 13 (8) ◽  
pp. 568
Author(s):  
Yi-Jhu Lu ◽  
Ya-Ju Wu ◽  
Lujen Chen ◽  
Bor-Sheng Ko ◽  
Tzu-Ching Chang ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Clinical Manifestations ◽  
Proximal Tubules ◽  
Tubulointerstitial Fibrosis ◽  
Advanced Chronic Kidney Disease ◽  
Renal Tubulointerstitial Fibrosis ◽  
Liver And Kidney ◽  
Hk2 Cells ◽  
Overall Mortality

Chronic kidney disease (CKD) is a commonly occurring complex renal syndrome that causes overall mortality in many diseases. The clinical manifestations of CKD include renal tubulointerstitial fibrosis and loss of renal function. Metallothionein-I/II (MT-I/II) is potentially expressed in the liver and kidney, and possesses antioxidant and metal detoxification properties. However, whether MT-I/II expression is associated with the prognosis of nephropathy remains unknown. In this study, we investigated the MT-I/II level in human CKD, using immunohistochemistry. MT-I/II is located on the proximal tubules and is notably reduced in patients with CKD. MT-I/II expression was significantly correlated with the functional and histological grades of CKD. In an aristolochic acid (AAI)-induced nephropathy mouse model, MT-I/II was abundantly increased after AAI injection for 7 days, but decreased subsequently compared to that induced in the acute phase when injected with AAI for 28 days. Furthermore, we found that ammonium pyrrolidinedithiocarbamate (PDTC) restored AAI-induced MT-I/II reduction in HK2 cells. The injection of PDTC ameliorated AAI-induced renal tubulointerstitial fibrosis and reduced the concentrations of blood urea nitrogen and creatinine in mouse sera. Taken together, our results indicate that MT-I/II reduction is associated with advanced CKD, and the retention of renal MT-I/II is a potential therapeutic strategy for CKD.

scholarly journals Targeted Inhibition of Gut Microbial Trimethylamine N-Oxide Production Reduces Renal Tubulointerstitial Fibrosis and Functional Impairment in a Murine Model of Chronic Kidney Disease

2020 ◽  
Vol 40 (5) ◽  
pp. 1239-1255 ◽  
Author(s):  
Nilaksh Gupta ◽  
Jennifer A. Buffa ◽  
Adam B. Roberts ◽  
Naseer Sangwan ◽  
Sarah M. Skye ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Renal Function ◽  
Kidney Disease ◽  
Gut Microbiota ◽  
Functional Impairment ◽  
Tubulointerstitial Fibrosis ◽  
Intestinal Microbes ◽  
Renal Tubulointerstitial Fibrosis ◽  
Selective Targeting ◽  
The Impact

Objective: Gut microbial metabolism of dietary choline, a nutrient abundant in a Western diet, produces trimethylamine (TMA) and the atherothrombosis- and fibrosis-promoting metabolite TMA-N-oxide (TMAO). Recent clinical and animal studies reveal that elevated TMAO levels are associated with heightened risks for both cardiovascular disease and incident chronic kidney disease development. Despite this, studies focusing on therapeutically targeting gut microbiota-dependent TMAO production and its impact on preserving renal function are limited. Approach and Results: Herein we examined the impact of pharmacological inhibition of choline diet-induced gut microbiota-dependent production of TMA, and consequently TMAO, on renal tubulointerstitial fibrosis and functional impairment in a model of chronic kidney disease. Initial studies with a gut microbial choline TMA-lyase mechanism-based inhibitor, iodomethylcholine, confirmed both marked suppression of TMA generation, and consequently TMAO levels, and selective targeting of the gut microbial compartment (ie, both accumulation of the drug in intestinal microbes and limited systemic exposure in the host). Dietary supplementation of either choline or TMAO significantly augmented multiple indices of renal functional impairment and fibrosis associated with chronic subcutaneous infusion of isoproterenol. However, the presence of the gut microbiota-targeting inhibitor iodomethylcholine blocked choline diet-induced elevation in TMAO, and both significantly improved decline in renal function, and significantly attenuated multiple indices of tubulointerstitial fibrosis. Iodomethylcholine treatment also reversed many choline diet-induced changes in cecal microbial community composition associated with TMAO and renal functional impairment. Conclusions: Selective targeting of gut microbiota-dependent TMAO generation may prevent adverse renal structural and functional alterations in subjects at risk for chronic kidney disease.

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.

Angiotensin II–Mediated Left Ventricular Abnormalities in Chronic Kidney Disease

2012 ◽  
Vol 60 (5) ◽  
pp. 785-791 ◽  
Author(s):  
Veena Raizada ◽  
Dustin Hillerson ◽  
Jaya Sheela Amaram ◽  
Betty Skipper
Keyword(s):  
Chronic Kidney Disease ◽  
Angiotensin Ii ◽  
Kidney Disease ◽  
Left Ventricular

scholarly journals Nephroprotective strategy in the treatment of hypertension as a modern general medical problem

2018 ◽  
pp. 107-118 ◽  
Author(s):  
V. I. Podzolkov ◽  
A. E. Bragina ◽  
T. I. Ishina ◽  
L. V. Bragina ◽  
L. V. Vasilyeva
Keyword(s):  
Chronic Kidney Disease ◽  
Angiotensin Ii ◽  
Kidney Disease ◽  
Renal Dysfunction ◽  
Medical Problem ◽  
Angiotensin Ii Receptor Blocker ◽  
Angiotensin Ii Receptor ◽  
High Prevalence ◽  
Advanced Stages ◽  
Receptor Blockers

The current population is characterized by a high prevalence of risk factors for the development of chronic kidney disease: hypertension, diabetes, obesity, metabolic syndrome, physical inactivity, smoking. The development of severe complications and a close connection with potentially fatal cardiovascular disorders make this disease a socially and economically significant problem. Treatment of chronic kidney disease in advanced stages belong to nephrologist duties. However, the success of preventive interventions depends on the time of their onset, which makes it relevant to identify the disease. The use of nephroprotective approaches by physicians of different specialties (general practitioners, cardiologists, gerontologists, nephrologists, endocrinologists) can significantly improve the prognosis of both those at risk of developing renal dysfunction and the existing disease. The review presents data on the clinical and laboratory efficacy of angiotensin-renin blocker use, as well as the combination of angiotensin II receptor blockers with calcium antagonists. Using the combination of the angiotensin II receptor blocker irbesartan and amlodipine as an example, we demonstrated the possibilities of nephroprotective therapy in patients with renal dysfunction.

scholarly journals Daily Low-intensity Pulsed Ultrasound Ameliorates Renal Fibrosis and Inflammation in Experimental Hypertensive and Diabetic Nephropathy

Hypertension ◽  
2020 ◽  
Vol 76 (6) ◽  
pp. 1906-1914
Author(s):  
Yoshiki Aibara ◽  
Ayumu Nakashima ◽  
Ki-ichiro Kawano ◽  
Farina Mohamad Yusoff ◽  
Fumitaka Mizuki ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Renal Failure ◽  
Diabetic Nephropathy ◽  
Angiotensin Ii ◽  
Kidney Disease ◽  
Renal Fibrosis ◽  
Pulsed Ultrasound ◽  
Hypertensive Nephropathy ◽  
Low Intensity Pulsed Ultrasound ◽  
Low Intensity

The estimated morbidity rate of chronic kidney disease is 8% to 16% worldwide, and many patients with chronic kidney disease eventually develop renal failure. Thus, the development of new therapeutic strategies for preventing renal failure is crucial. In this study, we assessed the effects of daily low-intensity pulsed ultrasound (LIPUS) therapy on experimental hypertensive nephropathy and diabetic nephropathy. Unilateral nephrectomy and subcutaneous infusion of angiotensin II via osmotic mini-pumps were used to induce hypertensive nephropathy in mice. Immunohistochemistry revealed that daily LIPUS treatment ameliorated renal fibrosis and infiltration of inflammatory cells induced by angiotensin II. A similar therapeutic effect was also observed in mice with angiotensin II-induced hypertensive nephropathy in which splenectomy was performed. In addition, LIPUS treatment significantly decreased systolic blood pressure after 21 days. Subsequently, db/db mice with unilateral nephrectomy developed proteinuria; daily LIPUS treatment significantly reduced proteinuria after 42 days. In addition, immunohistochemistry revealed that renal fibrosis was significantly ameliorated by LIPUS treatment. Finally, LIPUS stimulation suppressed TGF-β1 (transforming growth factor-β1)-induced phosphorylation of Smad2 and Smad3 in HK-2 (human proximal tubular cell line) cells. LIPUS treatment may be a useful therapy for preventing the progression of renal fibrosis in patients with chronic kidney disease.

Renoprotective effects of angiotensin II receptor blocker, candesartan cilexetil, in patients with stage 4–5 chronic kidney disease

2008 ◽  
Vol 12 (4) ◽  
pp. 256-263 ◽  
Author(s):  
Yoshifuru Tamura ◽  
Masahiro Kosuga ◽  
Masahiro Yamashita ◽  
Satoru Tomioka ◽  
Michiko Sasaki ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Angiotensin Ii ◽  
Kidney Disease ◽  
Candesartan Cilexetil ◽  
Receptor Blocker ◽  
Angiotensin Ii Receptor Blocker ◽  
Angiotensin Ii Receptor ◽  
Stage 4
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