Abstract P028: Activation Of The Renin-angiotensin System Drives Renal Metabolic Abnormalities In Diabetic Nephropathy

Hypertension ◽  
2020 ◽  
Vol 76 (Suppl_1) ◽  
Author(s):  
Kengo Azushima ◽  
Jean Paul Kovalik ◽  
Jianhong Ching ◽  
Susan B Gurley ◽  
Thomas M Coffman
Keyword(s):  
Fatty Acid ◽  
Fatty Acid Metabolism ◽  
Acid Metabolism ◽  
Renin Angiotensin System ◽  
Tca Cycle ◽  
High Grade ◽  
Wild Type ◽  
Angiotensin System ◽  
Renin Angiotensin ◽  
Mitochondrial Fatty Acid

Activation of the renin-angiotensin system (RAS) is a major contributor to the pathogenesis of diabetic nephroathy (DN). However, the precise mechanisms of renoprotection associated with RAS blockade in DN are not entirely clear. The aim of this study is to examine whether metabolic effects of RAS blockade might contribute to renoprotection. We utilized a mouse model of DN combining severe type I diabetes (the Akita mutation) with a single-copy renin transgene (ReninTG) driven by the albumin promoter. Akita-ReninTG mice on a 129/Sv background (DN-susceptible mice) develop clinical features of human DN including high-grade albuminuria, renal interstitial inflammation and glomerulosclerosis, while Akita-ReninTG mice on a C57BL/6 background (DN-resistant mice) do not develop significant kidney disease. These two experimental groups were treated with the angiotensin receptor blocker (ARB) losartan 10 mg/kg/day for 12 weeks, and metabolic profiles in kidney tissues were examined using a targeted metabolomics assay. The DN-susceptible mice exhibited high-grade albuminuria that was significantly attenuated by ARB (Vehicle vs ARB: 1480±562 vs 193±42 μg/day, p =0.045), while DN-resistant mice had minimal albuminuria that was not affected by ARB (Vehicle vs ARB: 80±14 vs 75±14 μg/day, p =0.801). The metabolomics profiles of the DN-resistant mice were similar to C57BL/6 wild-type controls. By contrast, DN-susceptible mice exhibited broad reductions in even-chain acyl-carnitines and an abnormal profile of TCA cycle intermediates compared to 129/Sv wild-type controls, suggesting substantial impairments of renal mitochondrial fuel oxidation including altered fatty acid metabolism. RAS blockade had broad effects to correct this profile by increasing acetyl-carnitines generated from acetyl-CoA and concomitantly normalizing expression of genes associated with mitochondrial fatty acid metabolism including PPAR-α, PGC-1α, CPT1 and CPT2. ARB treatment restored TCA cycle activity to normal. These findings suggest that effects of RAS blockade re-establish normal fuel metabolism and mitochondrial fatty acid oxidation in kidney and may contribute to renoprotection.

scholarly journals Myostatin regulates fatty acid desaturation and fat deposition through MEF2C/miR222/SCD5 cascade in pigs

2020 ◽  
Vol 3 (1) ◽  
Author(s):  
Hongyan Ren ◽  
Wei Xiao ◽  
Xingliang Qin ◽  
Gangzhi Cai ◽  
Hao Chen ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Fatty Acid ◽  
Fatty Acid Metabolism ◽  
Acid Metabolism ◽  
Muscle Growth ◽  
Subcutaneous Fat ◽  
Fat Deposition ◽  
Wild Type ◽  
Binding Prediction ◽  
Stearoyl Coa Desaturase

Abstract Myostatin (MSTN), associated with the “double muscling” phenotype, affects muscle growth and fat deposition in animals, whereas how MSTN affects adipogenesis remains to be discovered. Here we show that MSTN can act through the MEF2C/miR222/SCD5 cascade to regulate fatty acid metabolism. We generated MSTN-knockout (KO) cloned Meishan pigs, which exhibits typical double muscling trait. We then sequenced transcriptome of subcutaneous fat tissues of wild-type (WT) and MSTN-KO pigs, and intersected the differentially expressed mRNAs and miRNAs to predict that stearoyl-CoA desaturase 5 (SCD5) is targeted by miR222. Transcription factor binding prediction showed that myogenic transcription factor 2C (MEF2C) potentially binds to the miR222 promoter. We hypothesized that MSTN-KO upregulates MEF2C and consequently increases the miR222 expression, which in turn targets SCD5 to suppress its translation. Biochemical, molecular and cellular experiments verified the existence of the cascade. This novel molecular pathway sheds light on new targets for genetic improvements in pigs.

scholarly journals Multi-omics Integration Analysis Robustly Predicts High-Grade Patient Survival and Identifies CPT1B Effect on Fatty Acid Metabolism in Bladder Cancer

2019 ◽  
Vol 25 (12) ◽  
pp. 3689-3701 ◽  
Author(s):  
Venkatrao Vantaku ◽  
Jianrong Dong ◽  
Chandrashekar R. Ambati ◽  
Dimuthu Perera ◽  
Sri Ramya Donepudi ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Fatty Acid ◽  
Fatty Acid Metabolism ◽  
Acid Metabolism ◽  
Patient Survival ◽  
High Grade ◽  
Omics Integration ◽  
Integration Analysis

scholarly journals Distinct Components of Janus Kinase/Signal Transducer and Activator of Transcription Signaling Pathway Mediate the Regulation of Systemic and Tissue Localized Renin-Angiotensin System

2004 ◽  
Vol 18 (4) ◽  
pp. 1033-1041 ◽  
Author(s):  
Yueling Guo ◽  
Eduardo Mascareno ◽  
M. A. Q. Siddiqui
Keyword(s):  
Angiotensin Ii ◽  
Mrna Level ◽  
Renin Angiotensin System ◽  
Janus Kinase ◽  
Luciferase Reporter ◽  
Luciferase Expression ◽  
Signal Transducer ◽  
Wild Type ◽  
Angiotensin System ◽  
Renin Angiotensin

Abstract In an attempt to demonstrate the linkage between the Janus kinase (Jak)/signal transducer and activator of transcription (STAT) signaling and the activity of the systemic or local renin-angiotensin system in vivo, we produced transgenic mice harboring angiotensinogen (ANG) promoter containing the wild-type or mutant STAT target site (St-domain) fused to the luciferase reporter. The ANG-promoter-driven luciferase expression was dependent upon phosphorylation of Jak2, as administration of tyrphostin AG490, a potent inhibitor of Jak2, down-regulated the ANG promoter activity and abolished the stimulated endogenous ANG mRNA level in the liver. Administration of angiotensin II peptide to the mice resulted in prominent expression of luciferase in the liver and heart of animals containing wild type St-domain, but not in transgenes with mutant St-domain. Angiotensin II-induced signaling caused activation of STAT proteins in the liver (systemic), the pattern of which was distinct from that in the heart (local). The inducible expression of ANG promoter appears to be mediated by physical association of p300 with STAT 5B in liver and STAT 3 and STAT 5A in heart. Taken together, these results point to the differences in signaling mechanisms in the circulating and localized renin-angiotensin system and identify at least two molecular steps, the tyrosyl phosphorylation of Jak2 and the STAT/St-domain interaction, as pivotal in the regulation of ANG gene transcription.

scholarly journals High grade glioblastoma is associated with aberrant expression of ZFP57, a protein involved in gene imprinting, and of CPT1A and CPT1C that regulate fatty acid metabolism

2014 ◽  
Vol 15 (6) ◽  
pp. 735-741 ◽  
Author(s):  
Alessandra Cirillo ◽  
Anna Di Salle ◽  
Orsolina Petillo ◽  
Mariarosa AB Melone ◽  
Giovanna Grimaldi ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Fatty Acid Metabolism ◽  
Acid Metabolism ◽  
High Grade ◽  
Aberrant Expression ◽  
Gene Imprinting

ID: 81: NANOFORMULATED COPPER/ZINC SUPEROXIDE DISMUTASE CAUSES MUSCLE METABOLIC ALTERATIONS AND IMPROVES SYSTEMIC INSULIN SENSITIVITY IN MICE

2016 ◽  
Vol 64 (4) ◽  
pp. 927.1-927
Author(s):  
G Natarajan ◽  
C Perriotte-Olson ◽  
CV Desouza ◽  
S Viswanathan ◽  
D Manickam ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Fatty Acid ◽  
Fatty Acid Metabolism ◽  
Acid Metabolism ◽  
De Novo ◽  
Tolerance Test ◽  
Copper Zinc Superoxide Dismutase ◽  
Zinc Superoxide Dismutase ◽  
Mitochondrial Fatty Acid ◽  
Copper Zinc

Oxidative stress mediates mitochondrial dysfunction and impairment of glucose metabolism in muscle thereby leading to systemic insulin resistance. In vivo studies have demonstrated that copper/zinc superoxide dismutase (Cu/ZnSOD)-deficient mice show oxidative damage in various organs including skeletal muscle. The objective of this study is to determine the role of nanoformulated Cu/ZnSOD (nanoSOD) in improving insulin sensitivity through effects inherent to muscle. Wild type mice were fed a standard chow diet for 10 weeks. A cohort of these mice received nanoSOD intraperitoneally at 1000 U/kg body weight once in two days for a period of 15 days. We noted that the fasting blood glucose level was significantly reduced in nanoSOD treated mice compared to control (P<0.05). Moreover, insulin tolerance test (ITT) revealed that nanoSOD treated mice showed improved glucose handling in response to insulin (0.75 U/kg body weight) compared to control mice. However, the response of these mice to acute glucose challenge as analyzed by glucose tolerance test was not different between groups. We next analyzed the muscle mRNA samples for genes involved in fatty acid metabolism. Interestingly, we noted that the expression of FASN and SREBP1, genes promoting fatty acid synthesis was significantly reduced in nanoSOD treated mice suggesting that de novo lipogenesis which can promote insulin resistance is reduced upon nanoSOD treatment. Further, the mRNA expression of PCX which promotes both gluconeogenesis and lipogenesis was significantly reduced (P<0.01) in nanoSOD treated mice compared to controls. Regarding genes regulating fatty acid metabolism, we noted that the expression of ACOX1, CPT1a, and CPT2, genes involved in mitochondrial fatty acid β-oxidation was reduced in nanoSOD treated mice. Interestingly, these metabolic changes were associated with reduced mRNA levels of inflammatory markers including TNFα, MMP12, and VCAM-1 in visceral adipose tissue in nanoSOD treated mice. However, in the liver, the mRNA level of genes involved in de novo lipogenesis and mitochondrial fatty acid β-oxidation was not altered upon nanoSOD treatment Taken together; our data demonstrate that nanoSOD improves systemic glucose handling which was associated with a reduction in de novo lipogenesis and fatty acid oxidation in muscle. Because fatty acid oversupply is a key mediator of muscle insulin resistance primarily via accumulation of fatty acid metabolites, our data suggest that changes in muscle fatty acid metabolism may play a role in mediating the effects of nanoSOD in improving systemic glucose handing and insulin resistance. .

Sign in / Sign up

Export Citation Format

Share Document