Angiotensin II type 1 receptor blockers decrease kynurenic acid production in rat kidney in vitro

Izabela Zakrocka,Tomasz Kocki,Artur Wnorowski,Krzysztof Jóźwiak,Katarzyna M Targowska-Duda,Waldemar A Turski

doi:10.1007/s00210-018-1572-7

Izabela Zakrocka, Tomasz Kocki + Show 4 more

Open Access

https://doi.org/10.1007/s00210-018-1572-7

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Abstract

Glutamate (GLU) mainly through N-methyl-d-aspartate (NMDA) receptors plays pivotal role in kidney function regulation. Kynurenic acid (KYNA), a GLU receptors antagonist, is synthesized from kynurenine by kynurenine aminotransferases (KATs). Previously, it was shown that angiotensin II type 1 receptor blockers (ARBs) decrease KYNA production in rat brain in vitro. The aim of this study was to examine the influence of six ARBs: candesartan, irbesartan, losartan, olmesartan, telmisartan, and valsartan on KYNA production on rat kidney in vitro. The effect of ARBs was determined in kidney homogenates and on isolated KAT II enzyme. Among tested ARBs, irbesartan was the most effective KYNA synthesis inhibitor with IC50 of 14.4 μM. Similar effects were observed after losartan (IC50 45.9 μM) and olmesartan administration (IC50 108.1 μM), whereas candesartan (IC50 475.3 μM), valsartan (IC50 513.9 μM), and telmisartan (IC50 669.5 μM) displayed lower activity in KYNA synthesis inhibition in rat kidney homogenates in vitro. On the other hand, valsartan (IC50 27.5 μM) was identified to be the strongest KAT II inhibitor in rat kidney in vitro. Candesartan, losartan, and telmisartan suppressed KAT II activity with IC50 equal to 83.2, 83.3, and 108.3 μM, respectively. Olmesartan and irbesartan were the weakest KAT II inhibitors with IC50 values of 237.4 and 809.9 μM, respectively. Moreover, molecular docking suggested that studied ARBs directly bind to an active site of KAT II. In conclusion, our results indicate that ARBs decrease KYNA synthesis in rat kidney through enzymatic inhibition of KAT II, which may have impact on kidney function.

Highlights

High intrarenal angiotensin II (Ang II) concentration, apart from its physiological actions, may contribute to kidney injury through vasoconstriction, podocyte damage, and induction of inflammation (Fukuda et al 2012)
De novo production of Kynurenic acid (KYNA) in rat kidney homogenate under standard conditions in the presence of 10 μM KYN was 9.37 ± 0.47 pmol/mg protein/2 h
Profiling of Aadat, Kyat3, and Got2 genes coding for kynurenine aminotransferases (KATs) II–KAT IV indicated that KATs are expressed at medium to high level in rat kidney

Summary

Introduction

High intrarenal angiotensin II (Ang II) concentration, apart from its physiological actions, may contribute to kidney injury through vasoconstriction, podocyte damage, and induction of inflammation (Fukuda et al 2012). It is known that glutamate (GLU) plays crucial role in renal functions (Dryer 2015). It contributes to acid-base regulation through ammonia excretion in response to hypertonicity or podocyte damage (Altintas et al 2014). In addition to wellknown role in central nervous system (CNS) disorders, KYNA possesses natriuretic properties (Bądzyńska et al 2014)

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