The activation of the kynurenine pathway in a rat model with renovascular hypertension

Abstract

Hypertension is a serious condition that can lead to many health problems. The mechanisms underlying this process are still not fully understood. The kynurenine pathway may be involved in the occurrence and progression of hypertension. The purpose of this study was to examine the activity of peripheral kynurenine pathway in rats with renovascular hypertension in Goldblatt 2K1C model. Hypertension was induced in the experimental groups by constricting the renal artery of the left kidney of the rats. Determination of tryptophan (Trp) and kynurenine pathway metabolites was assessed by high-performance liquid chromatography in plasma and tissues obtained at 4, 8, and 16 weeks after the surgical intervention or sham surgery. Levels of Ang II were evaluated using commercial immuno-enzymatic ELISA kits. Surgical treatment led to increased values of mean blood pressure and systolic blood pressure, whereas Trp concentrations were decreased in experimental animals compared to appropriate controls. Simultaneously, the considerable increment of kynurenine pathway components and a significant increase in the activity of tryptophan 2,3-dioxygenase were observed in rats with developed hypertension in comparison with controls. There were no differences between Ang II levels in controls and experimental groups. The inverse relationship was between plasma Trp and both SBP and Ang II values, and Trp independently affected Ang II concentrations in hypertensive rats. In contrast, tryptophan 2,3-dioxygenase activity and plasma kynurenine metabolites positively correlated with blood pressure values as well as with Ang II levels in these animals. Moreover, kynurenine was independently connected with MBP. Renovascular hypertension influences kynurenine pathway and leads to an imbalance in Trp and its metabolite levels. Tryptophan 2,3-dioxygenase and part of the kynurenine metabolites in plasma and tissues positively correlated with blood pressure values and Ang II levels. Although the mechanisms underlying this phenomenon are unclear, our experiment showed a link between renovascular hypertension and activation of kynurenine pathway. Impact statement As hypertension is a major health problem, our research has focused on the connection between the kynurenine pathway and hypertension. We assessed the levels of the main metabolites of dietary tryptophan and analyzed its levels in terms of high blood pressure. The results of our work indicated that in the renovascular rat's model of hypertension, an alteration of the kynurenine pathway occurred. According to our knowledge, this is the first study that has investigated in a comprehensive manner the alteration of the kynurenine pathway under the condition of elevated blood pressure. On the one hand, the work supports a better understanding of pathophysiological basics of the occurrence of hypertension, and on the other hand it provides potential opportunities to treat this disease.

Keywords: 2K1C Goldblatts’ model; Renovascular hypertension; angiotensin II; kynurenine pathway; rats; tryptophan metabolism.

Figure 1

The values of mean and systolic blood pressure (BP) in rats with renovascular hypertension (GLB) and controls (CON). CON4, CON8, and CON16—rats from control group after 4, 8, and 16 weeks of sham, respectively, GLB4, GLB8, and GLB 16—rats from experimental group after 4, 8, and 16 weeks of surgical induction of hypertension, respectively (***p < 0.001)

Figure 2

Changes in concentrations of tryptophan (Trp) and its metabolites: kynurenine (KYN), kynurenic acid (KYNA), 3-hydroxykynurenine (3HKYN) and anthranilic acid (AA) in plasma of rats with renovascular hypertension (GLB) and controls (CON). CON4, CON8, and CON16—rats from control group after 4, 8, and 16 weeks of sham surgery, respectively, GLB4, GLB8, and GLB 16—rats from experimental group after 4, 8, and 16 weeks of surgical induction of hypertension, respectively (**p < 0.01; ***p < 0.001)

Figure 3

Spearman’s correlations between angiotensin II (Ang II) concentrations and tryptophan (Trp), tryptophan 2,3-dioxygenase (TDO) activity, and kynurenine pathway metabolites: kynurenic acid (KYNA), and 3-hydroxykynurenine (3HKYN) in plasma of rats with renovascular hypertension

Figure 4

The plasma metabolism of tryptophan (Trp) via kynurenine (KYN) pathway in rats with renovascular hypertension during 4, 8, and 16 weeks of experiment. The results are presented as % of increase of compounds of kynurenine pathway or ratios—the quantitative relation between specific compounds of kynurenine pathway from experimental groups with renal hypertension. KYNA: kynurenic acid; 3HKYN: 3-hydroxykynurenine; AA: anthranilic acid