The AT1 Receptor Blocker Telmisartan Reduces Intestinal Mucus Thickness in Obese Mice

Laura Nickel; Annika Sünderhauf; Elias Rawish; Ines Stölting; Stefanie Derer; Christoph Thorns; Urte Matschl; Alaa Othman; Christian Sina; Walter Raasch

doi:10.3389/fphar.2022.815353

The AT1 Receptor Blocker Telmisartan Reduces Intestinal Mucus Thickness in Obese Mice

Front Pharmacol. 2022 Mar 31:13:815353. doi: 10.3389/fphar.2022.815353. eCollection 2022.

Authors

Laura Nickel^{1

2}, Annika Sünderhauf³, Elias Rawish^{1

2}, Ines Stölting¹, Stefanie Derer³, Christoph Thorns⁴, Urte Matschl⁵, Alaa Othman^{6

7}, Christian Sina³, Walter Raasch^{1

2

6}

Affiliations

¹ Institute of Experimental and Clinical Pharmacology and Toxicology, University of Lübeck, Lübeck, Germany.
² DZHK (German Centre for Cardiovascular Research), Partner Site Hamburg/Kiel/Lübeck, Lübeck, Germany.
³ Division of Nutritional Medicine, University Hospital Schleswig-Holstein, Lübeck, Germany.
⁴ Institute of Pathology, University of Lübeck, Lübeck, Germany.
⁵ Department Virus Immunology, Heinrich Pette Institute, Leibniz Institute for Experimental Virology, Hamburg, Germany.
⁶ CBBM (Centre of Brain, Behaviour and Metabolism), University of Lübeck, Lübeck, Germany.
⁷ Institute for Clinical Chemistry, University Hospital Zürich, Zürich, Germany.

Abstract

The angiotensin II (type 1) (AT₁) receptor blocker telmisartan (TEL) is beneficial for the treatment of individuals suffering from metabolic syndrome. As we have shown that TEL has an impact on gut microbiota, we investigated here whether TEL influences gut barrier function. C57BL/6N mice were fed with chow or high-fat diet (HFD) and treated with vehicle or TEL (8 mg/kg/day). Mucus thickness was determined by immunohistochemistry. Periodic Acid-Schiff staining allowed the number of goblet cells to be counted. Using western blots, qPCR, and immunohistochemistry, factors related to mucus biosynthesis (Muc2, St6galnac), proliferation (Ki-67), or necroptosis (Rip3) were measured. The influence on cell viability was determined in vitro by using losartan, as the water solubility of TEL was too low for in vitro experiments. Upon HFD, mice developed obesity as well as leptin and insulin resistance, which were prevented by TEL. Mucus thickness upon HFD-feeding was diminished. Independent of feeding, TEL additionally reduced mucus thickness. Numbers of goblet cells were not affected by HFD-feeding and TEL. St6galnac expression was increased by TEL. Rip3 was increased in TEL-treated and HFD-fed mice, while Ki-67 decreased. Cell viability was diminished by using >1 mM losartan. The anti-obese effect of TEL was associated with a decrease in mucus thickness, which was likely not related to a lower expression of Muc2 and goblet cells. A decrease in Ki-67 and increase in Rip3 indicates lower cell proliferation and increased necroptosis upon TEL. However, direct cell toxic effects are ruled out, as in vivo concentrations are lower than 1 mM.

Keywords: AT1 receptor antagonist; MUC2 gene expression; diet induced obesity (DIO); goblet cell; mucus thickness; necroptosis; obesity; telmisartan.