MyMedR

Displaying all 4 publications

Abstract:

Sort:

The superoxide dismutase mimetic tempol blunts diabetes-induced upregulation of NADPH oxidase and endoplasmic reticulum stress in a rat model of diabetic nephropathy

De Blasio MJ, Ramalingam A, Cao AH, Prakoso D, Ye JM, Pickering R, et al.

Eur J Pharmacol, 2017 Jul 15;807:12-20.
PMID: 28438648 DOI: 10.1016/j.ejphar.2017.04.026

Endoplasmic reticulum (ER) stress contributes to progression of diabetic nephropathy, which promotes end-stage renal failure in diabetic patients. This study was undertaken to investigate the actions of tempol and ramipril, pharmacological agents that target the consequences of NADPH oxidase, on diabetic nephropathy in a rat model of type 1 diabetes, with an emphasis on markers of ER stress. Male Sprague-Dawley rats were injected intravenously with a single bolus of streptozotocin (55mg/kg) to induce type 1 diabetes. An additional age-matched group of rats was administered with citrate vehicle as controls. After 4 weeks of untreated diabetes, rats received tempol (1.5mM/kg/day subcutaneously, n=8), ramipril (1mg/kg/day in drinking water, n=8) or remained untreated for an additional 4 weeks (n=7). After 8 weeks of diabetes in total, kidneys were collected for histological analysis, gene expression and protein abundance. Tempol and ramipril blunted diabetes-induced upregulation of NADPH oxidase isoforms (Nox4, Nox2, p47phox), accompanied by an amelioration of diabetes-induced glomerular injury (podocin, nephrin, Kim-1), tubulo-interstitial fibrosis (TGFβ1, TGFβ-R2, pSMAD3, α-SMA) and pro-inflammatory cytokines (TNFα, MCP-1, ANX-A1, FPR2) expression. In addition, the diabetes-induced renal ER stress, evidenced by increased expression of GRP-78 chaperone and stress-associated markers ATF4, TRB3, as well as XBP1s, phospho-p38 mitogen-activated protein kinase (MAPK) and 3-nitrotyrosination, were all attenuated by tempol and ramipril. These observations suggest that antioxidant approaches that blunt NADPH upregulation may attenuate diabetic nephropathy, at least in part by negatively regulating ER stress and inflammation, and hence ameliorating kidney damage.
Fulltext Essential Hypertension Is Associated With Changes in Gut Microbial Metabolic Pathways: A Multisite Analysis of Ambulatory Blood Pressure

Nakai M, Ribeiro RV, Stevens BR, Gill P, Muralitharan RR, Yiallourou S, et al.

Hypertension, 2021 09;78(3):804-815.
PMID: 34333988 DOI: 10.1161/HYPERTENSIONAHA.121.17288

[Figure: see text].
Renal ACE2 (Angiotensin-Converting Enzyme 2) Expression Is Modulated by Dietary Fiber Intake, Gut Microbiota, and Their Metabolites

Snelson M, R Muralitharan R, Dinakis E, Nakai M, Jama HA, Shihata WA, et al.

Hypertension, 2021 06;77(6):e53-e55.
PMID: 33866801 DOI: 10.1161/HYPERTENSIONAHA.121.17039
Fulltext Influence of angiotensin II on the gut microbiome: modest effects in comparison to experimental factors

R Muralitharan R, Nakai ME, Snelson M, Zheng T, Dinakis E, Xie L, et al.

Cardiovasc Res, 2024 Sep 02;120(10):1155-1163.
PMID: 38518247 DOI: 10.1093/cvr/cvae062

AIMS: Animal models are regularly used to test the role of the gut microbiome in hypertension. Small-scale pre-clinical studies have investigated changes to the gut microbiome in the angiotensin II hypertensive model. However, the gut microbiome is influenced by internal and external experimental factors, which are not regularly considered in the study design. Once these factors are accounted for, it is unclear if microbiome signatures are reproduceable. We aimed to determine the influence of angiotensin II treatment on the gut microbiome using a large and diverse cohort of mice and to quantify the magnitude by which other factors contribute to microbiome variations.
METHODS AND RESULTS: We conducted a retrospective study to establish a diverse mouse cohort resembling large human studies. We sequenced the V4 region of the 16S rRNA gene from 538 samples across the gastrointestinal tract of 303 male and female C57BL/6J mice randomized into sham or angiotensin II treatment from different genotypes, diets, animal facilities, and age groups. Analysing over 17 million sequencing reads, we observed that angiotensin II treatment influenced α-diversity (P = 0.0137) and β-diversity (i.e. composition of the microbiome, P < 0.001). Bacterial abundance analysis revealed patterns consistent with a reduction in short-chain fatty acid producers, microbial metabolites that lower blood pressure. Furthermore, animal facility, genotype, diet, age, sex, intestinal sampling site, and sequencing batch had significant effects on both α- and β-diversity (all P < 0.001). Sampling site (6.8%) and diet (6%) had the largest impact on the microbiome, while angiotensin II and sex had the smallest effect (each 0.4%).
CONCLUSION: Our large-scale data confirmed findings from small-scale studies that angiotensin II impacted the gut microbiome. However, this effect was modest relative to most of the other factors studied. Accounting for these factors in future pre-clinical hypertensive studies will increase the likelihood that microbiome findings are replicable and translatable.