The antiobese effect of AT1 receptor blockade is augmented in mice lacking Mas

Dapper, Carla; Schuster, Frank; Stölting, Ines; Vogt, Florian; Souza, Lucas Araújo Castro E; Alenina, Natalia; Bäder, Michael; Raasch, Walter

doi:10.1007/s00210-019-01643-0

Cited by 7 publications

(17 citation statements)

References 76 publications

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“…However, ablation of Mas in C57BL/6 mice produced only minor changes in glucose and lipid metabolism, although cholesterol levels were elevated in old mice 16 . Diet-induced obesity was less pronounced in Mas-knockout FVB/N than in widetype mice 17 . Similar to this, our Mas −/− mice in C57BL/6 showed unchanged lipid profile.…”

Section: Discussionmentioning

confidence: 82%

“…The role of Ang (1-7)/Mas receptor signaling pathway in obesity-related kidney diseases also remains clarified. Mas deficiency was shown to lead to metabolic abnormalities, e.g., dyslipidemia and type 2 diabetes in FVB/N mice 16 , but in another studies, diet-induced obesity was less pronounced in Masknockout FVB/N than in wild type mice 17 , and Mas deficiency in C57BL/6 mice have no effect on lipid metabolism 18 .…”

Section: Introductionmentioning

confidence: 98%

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Tubular Mas receptor mediates lipid-induced kidney injury

et al. 2021

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Obesity-related kidney diseases are becoming serious health problems worldwide, yet the mechanism by which obesity causes kidney injury is not fully understood. The purpose of current study was to investigate the role of Mas receptor in lipid-induced kidney injury. In mice fed with high-fat diet (HFD), the protein abundance of markers of autophagy, endoplasmic reticulum stress (ER stress) and apoptosis was dramatically increased in the kidney cortex, which was markedly prevented by Mas deletion (Mas−/−) or Mas receptor antagonist A779. Palmitic acid (PA) induced persistently increased autophagy, ER stress, and apoptosis as well as mitochondrial injuries in primary cultured proximal tubular cells from wild type, but not from Mas−/− mice. In human proximal tubular HK2 cells, PA-induced autophagy and ER stress was aggravated by Mas agonists Ang (1–7) or AVE0991, but attenuated by A779 or Mas knockdown. Stimulation of Mas resulted in elevated intracellular calcium levels [Ca2+]i in HK2 cells treated with PA, whereas inhibition or knockdown of Mas decreased [Ca2+]i. Mitochondrial outer membrane located voltage-dependent anion channel (VDAC1) was markedly upregulated in HK2 cells treated with PA, which was associated with impaired mitochondrial morphology and depolarization. These were enhanced by AVE0991 and suppressed by A779 or Mas knockdown. Mas knockdown in HK2 cells prevented impaired interactions among VDAC1, autophagy adaptor P62, and ubiquitin, induced by PA, leading to a potential ubiquitination of VDAC1. In conclusion, Mas receptor-mediated lipid-induced impaired autophagy and ER stress in the kidney, likely contributing to tubular injuries in obesity-related kidney diseases.

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Section: Discussionmentioning

confidence: 82%

Section: Introductionmentioning

confidence: 98%

Tubular Mas receptor mediates lipid-induced kidney injury

et al. 2021

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“…Once a day, mice received TEL (8 mg/kg bw ) or vehicle by oral gavage in a volume of 5 µL/g body weight. TEL dosages were evaluated recently (Muller-Fielitz et al 2012) and have been confirmed in numerous studies both in rats (Miesel et al 2012, Muller-Fielitz et al 2014, Schuchard et al 2015, Winkler et al 2016, Gustaityte et al 2018 and in mice (Schuster et al 2018, Dapper et al 2019 to reveal antiobese effects. For administration, TEL was suspended in 10% gum arabic (Carl Roth GmbH, Karlsruhe, Germany), resulting in a suspension of 1.6 mg/mL TEL.…”

Section: Study Protocol (Part 1)mentioning

confidence: 96%

“…Data were analyzed separately for light and dark periods (only considering a core period of 8 h for each period) and averaged for the 5 days. At w7, insulin sensitivity was determined by performing an insulin tolerance test (ITT) as recently described (Schuster et al 2018, Dapper et al 2019. To validate leptin sensitivity, a leptin resistance test (LRT) was performed at w8 (Dapper et al 2019).…”

Section: Study Protocol (Part 1)mentioning

confidence: 99%

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Telmisartan prevents development of obesity and normalizes hypothalamic lipid droplets

Rawish

Nickel

Schuster

et al. 2020

Journal of Endocrinology

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The AT1 receptor blocker telmisartan (TEL) prevents diet-induced obesity. Hypothalamic lipid metabolism is functionally important for energy homeostasis, as a surplus of lipids induces an inflammatory response in the hypothalamus, thus promoting the development of central leptin resistance. However, it is unclear as to whether TEL treatment affects the lipid status in the hypothalamus. C57BL/6N mice were fed with chow (CONchow) or high-fat diet (CONHFD). HFD-fed mice were gavaged with TEL (8 mg/kg/day, 12 weeks, TELHFD). Mice were phenotyped regarding weight gain, energy homeostasis, and glucose control. Hypothalamic lipid droplets were analyzed by fluorescence microscopy. Lipidomics were assessed by performing liquid chromatography-mass spectrometry in plasma and hypothalami. Adipokines were investigated using immunosorbent assays. Glial fibrillary acidic protein (GFAP) was determined by Western blotting and immunohistochemical imaging. We found that body weight, energy homeostasis, and glucose control of TEL-treated mice remained normal while CONHFD became obese. Hypothalamic ceramide and triglyceride levels as well as alkyne oleate distribution were normalized in TELHFD. The lipid droplet signal in the tanycyte layer was higher in CONHFD than in CONchow and returned to normal under TELHFD conditions. High hypothalamic levels of GFAP protein indicate astrogliosis of CONHFD mice while normalized GFAP, TNFα, and IL1α levels of TELHFD mice suggest that TEL prevents hypothalamic inflammation. In conclusion, TEL has anti-obese efficacy and prevented lipid accumulation and lipotoxicity, which is accompanied by an anti-inflammatory effect in the murine hypothalamus. Our findings support the notion that a brain-related mechanism is involved in TEL-induced weight loss.

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Diverse biological functions of the renin‐angiotensin system

Rao,

Bhat,

Shibata

et al. 2023

Medicinal Research Reviews

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The renin‐angiotensin system (RAS) has been widely known as a circulating endocrine system involved in the control of blood pressure. However, components of RAS have been found to be localized in rather unexpected sites in the body including the kidneys, brain, bone marrow, immune cells, and reproductive system. These discoveries have led to steady, growing evidence of the existence of independent tissue RAS specific to several parts of the body. It is important to understand how RAS regulates these systems for a variety of reasons: It gives a better overall picture of human physiology, helps to understand and mitigate the unintended consequences of RAS‐inhibiting or activating drugs, and sets the stage for potential new therapies for a variety of ailments. This review fulfills the need for an updated overview of knowledge about local tissue RAS in several bodily systems, including their components, functions, and medical implications.

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The antiobese effect of AT1 receptor blockade is augmented in mice lacking Mas

Cited by 7 publications

References 76 publications

Tubular Mas receptor mediates lipid-induced kidney injury

Tubular Mas receptor mediates lipid-induced kidney injury

Telmisartan prevents development of obesity and normalizes hypothalamic lipid droplets

Diverse biological functions of the renin‐angiotensin system

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