scholarly journals Enteropeptidase inhibitor SCO-792 effectively prevents kidney function decline and fibrosis in a rat model of chronic kidney disease

2020 ◽  
Author(s):  
Yuko Katayama ◽  
Jun Sugama ◽  
Tomohisa Suzuki ◽  
Yoshimasa Ishimura ◽  
Akihiro Kobayashi ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Kidney Function ◽  
Therapeutic Potential ◽  
Renal Plasma Flow ◽  
Production Capacity ◽  
Therapeutic Effects ◽  
Kidney Fibrosis ◽  
Obesity And Diabetes ◽  
Gfr Decline

Abstract Background Inhibiting enteropeptidase, a gut serine protease regulating protein digestion, suppresses food intake and ameliorates obesity and diabetes in mice. However, the effects of enteropeptidase inhibition on the kidney parameters are largely unknown. Here, we evaluated the chronic effects of an enteropeptidase inhibitor, SCO-792, on kidney function, albuminuria, and kidney pathology in spontaneously hypercholesterolaemic (SHC) rats, a rat chronic kidney disease (CKD) model. Methods SCO-792, an orally available enteropeptidase inhibitor, was administered (0.03% and 0.06% (w/w) in the diet) for five weeks to 20-week-old SHC rats showing albuminuria and progressive decline in glomerular filtration rate (GFR). The effects of SCO-792 and the contribution of amino acids to these effects were evaluated. Results SCO-792 increased the faecal protein content, indicating that SCO-792 inhibited enteropeptidase in SHC rats. Chronic treatment with SCO-792 prevented GFR decline and suppressed albuminuria. Moreover, SCO-792 improved glomerulosclerosis and kidney fibrosis. Pair feeding with SCO-792 (0.06%) was less effective in preventing GFR decline, albuminuria, and renal histological damage than SCO-792 treatment, indicating the enteropeptidase-inhibition-dependent therapeutic effects of SCO-792. SCO-792 did not affect the renal plasma flow, suggesting that its effect on GFR was mediated by an improvement in filtration fraction. Moreover, SCO-792 increased hydrogen sulphide production capacity, which has a role in tissue protection. Finally, methionine and cysteine supplementation to the diet abrogated SCO-792-induced therapeutic effects on albuminuria. Conclusions SCO-792-mediated inhibition of enteropeptidase potently prevented GFR decline, albuminuria, and kidney fibrosis; hence, it may have therapeutic potential against CKD.

scholarly journals Cannabinoid Receptor 1 Inhibition in Chronic Kidney Disease: A New Therapeutic Toolbox

2021 ◽  
Vol 12 ◽  
Author(s):  
Myriam Dao ◽  
Helene François
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Renal Fibrosis ◽  
Cannabinoid Receptor ◽  
Therapeutic Potential ◽  
Present Review ◽  
Renal Physiology ◽  
Sodium Balance ◽  
Obesity And Diabetes

Chronic kidney disease (CKD) concerns millions of individuals worldwide, with few therapeutic strategies available to date. Recent evidence suggests that the endocannabinoid system (ECS) could be a new therapeutic target to prevent CKD. ECS combines receptors, cannabinoid receptor type 1 (CB1R) and type 2 (CB2R), and ligands. The most prominent receptor within the kidney is CB1R, its endogenous local ligands being anandamide and 2-arachidonoylglycerol. Therefore, the present review focuses on the therapeutic potential of CB1R and not CB2R. In the normal kidney, CB1R is expressed in many cell types, especially in the vasculature where it contributes to the regulation of renal hemodynamics. CB1R could also participate to water and sodium balance and to blood pressure regulation but its precise role remains to decipher. CB1R promotes renal fibrosis in both metabolic and non-metabolic nephropathies. In metabolic syndrome, obesity and diabetes, CB1R inhibition not only improves metabolic parameters, but also exerts a direct role in preventing renal fibrosis. In non-metabolic nephropathies, its inhibition reduces the development of renal fibrosis. There is a growing interest of the industry to develop new CB1R antagonists without central nervous side-effects. Experimental data on renal fibrosis are encouraging and some molecules are currently under early-stage clinical phases (phases I and IIa studies). In the present review, we will first describe the role of the endocannabinoid receptors, especially CB1R, in renal physiology. We will next explore the role of endocannabinoid receptors in both metabolic and non-metabolic CKD and renal fibrosis. Finally, we will discuss the therapeutic potential of CB1R inhibition using the new pharmacological approaches. Overall, the new pharmacological blockers of CB1R could provide an additional therapeutic toolbox in the management of CKD and renal fibrosis from both metabolic and non-metabolic origin.

scholarly journals Lanthanum Hydroxide Protects Kidney Through Gut-Metabolite-Kidney Axis in a Rat Model of CKD

2021 ◽  
Author(s):  
Yuan Gao ◽  
Shengnan Wang ◽  
Lijun Sun ◽  
Bing Li ◽  
Hong Liu ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Amino Acid ◽  
Kidney Disease ◽  
Kidney Function ◽  
Rat Model ◽  
Therapeutic Potential ◽  
Protective Role ◽  
Lanthanum Hydroxide ◽  
Microbial Dysbiosis ◽  
Amino Acid Imbalance

Abstract Background: Recent evidence suggests alterations in the gut-kidney axis may drive chronic kidney disease (CKD). Results: In the present study, we observed that administration of adenine to rats induced CKD, gut microbial dysbiosis, kidney pathology, and amino acid metabolism. In this model of CKD hyperphosphatemia, lanthanum hydroxide improved kidney function in CKD rats by restoring gut microbial homeostasis, thereby increasing urine ammonium metabolism. These findings demonstrated that lanthanum hydroxide improves kidney function in a CKD model in mice by restoring homeostasis of the gut-metabolite-kidney axis, which alleviated an amino acid imbalance. Lanthanum hydroxide thus shows therapeutic potential for patients with CKD, through reshaping the composition of gut microbiota.Conclusions: Lanthanum hydroxide plays a kidney protective role through the gut-metabolite-kidney axis in a rat model of chronic kidney disease caused by adenine.

scholarly journals MicroRNA in kidney disease

2016 ◽  
Vol 14 (1) ◽  
pp. 8-10 ◽  
Author(s):  
Ingrid Prkacin ◽  
Gordana Cavric ◽  
Nikolina Basic-Jukic
Keyword(s):  
Chronic Kidney Disease ◽  
Growth Factor ◽  
Kidney Disease ◽  
Transforming Growth Factor Beta ◽  
Kidney Development ◽  
Transforming Growth Factor ◽  
Therapeutic Potential ◽  
Kidney Diseases ◽  
Kidney Fibrosis ◽  
Growth Factor Beta

AbstractClinical and laboratory findings of kidney disease in an adult may find an explanation in kidney functional and/or structural abnormalities that already existed during infancy and childhood, but that may have been missed or underdiagnosed. All the cardiovascular abnormalities that occur in adults with chronic kidney disease are also present in children with chronic kidney disease. Complications in childhood chronic kidney disease will have consequences well beyond pediatric age and influence outcomes of affected young adults with disease. Kidney dysfunction appears early in the course of kidney disease and has been observed in children and adults with chronic kidney disease, condition characterised with kidney fibrosis. Transforming growth factor beta is recognized as a major mediator of kidney fibrosis. New evidence illustrates the relationship between transforming growth factor beta signaling and microRNAs expression during kidney diseases development. MicroRNAs play important roles in kidney development and kidney diseases; they are naturally occurring, 22-nucleotide, noncoding RNAs that mediate posttranscriptional gene regulation. Dysregulation of miRNA expression is an indicator of several diseases including chronic kidney disease. Targeting microRNAs should be a therapeutic potential to ameliorate the disease related to fibrosis. The discovery that circulating miRNAs are detectable in serum and plasma, and that their expression varies as a result of disease, presents great potential to be used as biomarkers in kidney disease prevention and diagnosis.

scholarly journals Induction of AMPK activity corrects early pathophysiological alterations in the subtotal nephrectomy model of chronic kidney disease

2013 ◽  
Vol 305 (5) ◽  
pp. F727-F733 ◽  
Author(s):  
Joseph Satriano ◽  
Kumar Sharma ◽  
Roland C. Blantz ◽  
Aihua Deng
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Kidney Function ◽  
Rat Kidney ◽  
Metabolic Efficiency ◽  
Loss Of Function ◽  
Kidney Fibrosis ◽  
Subtotal Nephrectomy ◽  
Progression Of Disease ◽  
Ampk Activity

The rat kidney ablation and infarction (A/I) model of subtotal or 5/6th nephrectomy is the most commonly studied model of nondiabetic chronic kidney disease (CKD). The A/I kidney at 1 wk exhibits reductions in kidney function, as determined by glomerular filtration rate, and diminished metabolic efficiency as determined by oxygen consumption per sodium transport (QO2/TNa). As renoprotective AMPK activity is affected by metabolic changes and cellular stress, we evaluated AMPK activity in this model system. We show that these early pathophysiological changes are accompanied by a paradoxical decrease in AMPK activity. Over time, these kidney parameters progressively worsen with extensive kidney structural, functional, metabolic, and fibrotic changes observed at 4 wk after A/I. We show that induction of AMPK activity with either metformin or 5-aminoimidazole-4-carboxamide ribonucleotide increases AMPK activity in this model and also corrects kidney metabolic inefficiency, improves kidney function, and ameliorates kidney fibrosis and structural alterations. We conclude that AMPK activity is reduced in the subtotal nephrectomy model of nondiabetic CKD, that altered regulation of AMPK is coincident with the progression of disease parameters, and that restoration of AMPK activity can suppress the progressive loss of function characteristic of this model. We propose that induction of AMPK activity may prove an effective therapeutic target for the treatment of nondiabetic CKD.

scholarly journals [68 Ga]Ga-FAPI uptake correlates with the state of chronic kidney disease

2022 ◽  
Author(s):  
Patrick Conen ◽  
Francesca Pennetta ◽  
Katharina Dendl ◽  
Fabian Hertel ◽  
Andreas Vogg ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Kidney Function ◽  
Negative Correlation ◽  
Background Activity ◽  
Renal Parenchyma ◽  
Diagnostic Tools ◽  
Kidney Fibrosis ◽  
Radiotracer Uptake ◽  
Ckd Stage

Abstract Purpose Kidney fibrosis leads to a progressive reduction in kidney function ultimately resulting in kidney failure. Diagnostic tools to detect kidney fibrosis are all invasive in nature requiring kidney biopsies with subsequent histological validation. In this retrospective study, the diagnostic value of three different radiotracers for the noninvasive prediction of kidney fibrosis was analyzed, taking into account the glomerular filtration rate (GFR) and the intra-renal parenchymal radiotracer uptake. Methods In 81 patients receiving either one of the following molecular imaging probes, [68 Ga]Ga-FAPI, [68 Ga]Ga-PSMA, or [68 Ga]Ga-DOTATOC, kidney function parameters were correlated with SUVmax and SUVmean of the renal parenchyma and background activity measured in lung parenchyma, myocardium, gluteal muscle, and the abdominal aorta. Patients were clustered according to their grade of chronic kidney disease (CKD), and a regression analysis and one-way ANOVA were conducted in this retrospective analysis. Results We found a negative correlation between GFR and [68 Ga]Ga-FAPI uptake for both SUVmax and SUVmean values, whereas background activity showed no correlation with GFR. [68 Ga]Ga-DOTATOC and [68 Ga]Ga-PSMA did not correlate between CKD stage and intra-renal parenchymal radiotracer uptake. Only [68 Ga]Ga-PSMA background activity exhibited a positive correlation with GFR suggesting an unspecific binding/retention potentially due to longer circulation times. Conclusion There is a significant negative correlation between renal parenchymal [68 Ga]Ga-FAPI uptake and GFR, which was not the case for [68 Ga]Ga-DOTATOC and [68 Ga]Ga-PSMA. This correlation suggests a specific binding of FAPI rather than a potential unspecific retention in the renal parenchyma, underlining the potential value of [68 Ga]Ga-FAPI for the noninvasive quantitative evaluation of kidney fibrosis.

scholarly journals Lipocalin 2 stimulates bone fibroblast growth factor 23 production in chronic kidney disease

Bone Research ◽  
2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Guillaume Courbon ◽  
Connor Francis ◽  
Claire Gerber ◽  
Samantha Neuburg ◽  
Xueyan Wang ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Growth Factor ◽  
Kidney Disease ◽  
Iron Deficiency ◽  
Fibroblast Growth Factor ◽  
Kidney Function ◽  
Fibroblast Growth Factor 23 ◽  
Left Ventricular ◽  
Fibroblast Growth ◽  
Lipocalin 2

AbstractBone-produced fibroblast growth factor 23 (FGF23) increases in response to inflammation and iron deficiency and contributes to cardiovascular mortality in chronic kidney disease (CKD). Neutrophil gelatinase-associated lipocalin (NGAL or lipocalin 2; LCN2 the murine homolog) is a pro-inflammatory and iron-shuttling molecule that is secreted in response to kidney injury and may promote CKD progression. We investigated bone FGF23 regulation by circulating LCN2. At 23 weeks, Col4a3KO mice showed impaired kidney function, increased levels of kidney and serum LCN2, increased bone and serum FGF23, anemia, and left ventricular hypertrophy (LVH). Deletion of Lcn2 in CKD mice did not improve kidney function or anemia but prevented the development of LVH and improved survival in association with marked reductions in serum FGF23. Lcn2 deletion specifically prevented FGF23 elevations in response to inflammation, but not iron deficiency or phosphate, and administration of LCN2 increased serum FGF23 in healthy and CKD mice by stimulating Fgf23 transcription via activation of cAMP-mediated signaling in bone cells. These results show that kidney-produced LCN2 is an important mediator of increased FGF23 production by bone in response to inflammation and in CKD. LCN2 inhibition might represent a potential therapeutic approach to lower FGF23 and improve outcomes in CKD.

scholarly journals Everyday Discrimination and Kidney Function Among Older Adults: Evidence From the Health and Retirement Study

2019 ◽  
Vol 75 (3) ◽  
pp. 517-521
Author(s):  
Ryon J Cobb ◽  
Roland J Thorpe ◽  
Keith C Norris
Keyword(s):  
Older Adults ◽  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Kidney Function ◽  
The United States ◽  
Health And Retirement Study ◽  
Disease Epidemiology ◽  
Lower Egfr ◽  
Everyday Discrimination ◽  
Retirement Study

Abstract Background With advancing age, there is an increase in the time of and number of experiences with psychosocial stressors that may lead to the initiation and/or progression of chronic kidney disease (CKD). Our study tests whether one type of experience, everyday discrimination, predicts kidney function among middle and older adults. Methods The data were from 10 973 respondents (ages 52–100) in the 2006/2008 Health and Retirement Study, an ongoing biennial nationally representative survey of older adults in the United States. Estimated glomerular filtration rate (eGFR) derives from the Chronic Kidney Disease Epidemiology Collaboration equation. Our indicator of everyday discrimination is drawn from self-reports from respondents. Ordinary Least Squared regression (OLS) models with robust standard errors are applied to test hypotheses regarding the link between everyday discrimination and kidney function. Results Everyday discrimination was associated with poorer kidney function among respondents in our study. Respondents with higher everyday discrimination scores had lower eGFR after adjusting for demographic characteristics (B = −1.35, p < .05), and while attenuated, remained significant (B = −0.79, p < .05) after further adjustments for clinical, health behavior, and socioeconomic covariates. Conclusions Our study suggests everyday discrimination is independently associated with lower eGFR. These findings highlight the importance of psychosocial factors in predicting insufficiency in kidney function among middle-aged and older adults.

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