The association of urinary prostaglandins with uric acid in hyperuricemia patients

Uric acid (UA) is the final product of purine metabolism [1]. High UA levels are known to be a risk factor for diabetes, Chronic kidney disease (CKD), and various cardiovascular diseases [2]. According to the data from the China National Health Survey (CNHS),the prevalence of hyperuricemia(HUA) was as high as 25.1% in men and 15.9% in women in mainland China [3], becoming a major public health problem and threatening public health. In recent decades, uric acid has attracted extensive interest because of the various peculiarities. Studies over the past two decades show that uric acid play a part in the oxidative stress, endothelial dysfunction and inflammation response [4‐6]. Existing researches have suggested that uric acid is a risk factor for the development of chronic kidney disease by damaging renal tubule cells and affecting endothelial function and thus renal hemodynamics, however, the mechanism of how uric acid may affect renal hemodynamics is currently unknown.

Prostaglandins (PGs) are important lipid mediators produced from arachidonic acid via the sequential catalyzation of cyclooxygenases and specific prostaglandin synthases and PGs exert distinct roles by combining to a diverse family of membrane-spanning G protein-coupled prostanoid receptors [7]. As a kind of indispensable lipid mediator in human body, PGs are important in numerous physiological and pathophysiological processes. In the previous studies, considerable attention has been paid to inflammatory responses of prostaglandins. Under physiological situation, PGs play an important role in the regulation of renal hemodynamics, renin release, as well as water and salt balance [8‐10]. Some in vitro studies have shown that uric acid may affect the release of cellular prostaglandins [11]. But the results have not been confirmed in patients.

Therefore, we made a reasonable hypothesis that renal local uric acid handling may be correlated with prostaglandins levels in hyperuricemia patients. Hence, the research was designed to study the association of uric acid with prostaglandins.

In our study, we found that SUA was negatively correlated with urinary PGE2, and Cua was positively associated with urinary PGE2.PGE2 was significantly different between different SUA and Cua groups.

Prostaglandin E2(PGE2) is the main product catalyzed synthesis of arachidonic acid through the cycloxidase metabolic pathway, and is highly synthesized in the kidney [16]. Initially, it was widely believed that renal water transport was regulated solely by the hypothalamic production of arginine vasopressin (AVP), also known as antidiuretic hormone [17, 18]. However, abundant evidence suggests that PGE2 also plays an important role in regulating renal collecting tube substance reabsorption. Studies in humans and rodents have found that Cox-2 expression is significantly increased in the dense macula and the thick ascending ramus of cortex when effective blood volume decreases, and its main inducible substances such as PGE2 act on the glomeruli to counter the vasoconstriction effect of endogenous vasoactive substances [19]. In addition to improving renal microcirculation, PGE2 synthesized in the dense plaques can also increase renin release [20]. The release of renin caused by PGE2 mainly occurs in isolated paraglomerular organ (JAG) cells, and its action may be related to the cAMP signal transduction pathway mediated by EP2 or EP4 receptor, but the specific molecular mechanism needs to be further studied. It has been found in animal experiments that EP1 receptor can regulate aquaporin and sodium transporter in kidney, weaken AVP-induced water transport and inhibit sodium transport in mouse collecting tubes, which is mediated by ENaC and Pendrin pathways [21]. A previous study has showed that the kidney PGE2 level is higher in hyperuricemia rat [22].Some other studies have found that high uric acid level can cause the thickening of the afferent arterioles, or impairs the autoregulatory response of the afferent arterioles, producing renal hypoperfusion [23, 24], this sequence of reactions may lead to the activation of RAAS, which in turn leads to the elevation of PGE2.Incresed PGE2 can increase the Tubuloglomerular feedback(TGF) sensitivity [25]. Activation of tubule feedback leads to further elevation of uric acid levels. Urine sodium excretion is positively correlated with urine uric acid excretion [26], which is consistent with our previous studies [27], and FEua is positively correlated with FENa. Therefore, PGE2 may also affect the transport of uric acid in the kidney, and the specific mechanism needs to be further elucidated. In addition to PGE2, other prostaglandins are present in our body. TXA2 and PGI2 are unstable and quickly degrade to TXB2 and 6-keto-PGFLA in aqueous solution. TXA2(TXB2) and PGl2(6-keto-PGF1a) form a pair of biological activities, but are mutually restricted, and are important substances to maintain the stability of the internal environment [28]. The stable metabolites TXB2 and 6-keto-PGF1A could reflect the ratio of TXA2 to PGI2. TXA2 is a vasoconstrictor [29, 30], which plays a key role in the regulation of renal hemodynamics, determined by the use of TP agonists (U-46,619) [31, 32]. A previous study reported that Angii-induced elevated levels of vasoceramide may be involved in the pathogenesis of renal injury through TXA2-mediated vasoconstriction [33, 34]. Another study supported this conclusion, suggesting that the AngII/AT1 receptor /nSMase/ ceramide—PLA2 /TXA2 pathway contributes to the regulation of renal vasoconstriction [35]. It is possible that the amount of TXA2, a vasoconstrictor, decreases and the amount of its metabolite TXB2 in urine decreases. However, further studies are needed to determine the extent to which FEua physiologically regulates the excretion of TXB2 during vascular motility.

Uric acid is mainly excreted in the kidney [36]. Some in vitro studies have found that PGE2 release of cells increases under the stimulation of uric acid [37, 38]. However, these experiments were not confirmed in vivo. After analyzing the urine of patients with hyperuricemia, we found that SUA was significantly negatively correlated with urinary PGE2, while Cua was positively correlated with urinary PGE2. When uric acid excretion increases, uric acid in renal tubules increases, which indicates that uric acid may promote PGE2 synthesis in renal tubular epithelial cells. These results are consistent with the results of previous study [11]. In individuals with the higher FEua and Cua may be accompanied by volume expansion. This can be briefly illustrated by a previous study [39], in which 19 subjects were performed with rapid infusion of hypo-, iso- or hypertonic saline and assessed the relative contributions of volume expansion and increased FENa to the uricosuria of saline infusion. As mentioned above, FEua is positively correlated with FENa, the relationship between FEua and FENa was entirely attributed to their correlation with infusion volume. In other words, individuals with higher FEua and Cua may have imperceptible volume expansion accompanied by less vasoconstriction compared to the lower FEua and Cua.

As far as we know, little results were found in the study on the question of the urinary excretion of prostaglandins based on the renal handling of uric acid. The importance and originality of this study are that it explores that there is an association between uric acid and urinary prostaglandins. Apparently, the present study naturally includes some limitations. A major source of limitation is due to small sample size, which may give rise to considerable deviations. In addition, normal SUA people and women are not included in this study. Finally, the mechanism of the urinary prostaglandins and urinary uric acid is not further studied.

Our findings provide evidence that SUA was negatively correlated with urinary PGE2, and Cua was positively correlated with urinary PGE2. Urinary PGE2 was significantly different between different SUA and Cua groups. It is suggested that uric acid may be correlated with urinary prostaglandin excretion in patients with hyperuricemia, which further suggests one of the possible causes of abnormal renal hemodynamics in hyperuricemia. Here we bring together much of this work, which has so far only scratched the surface of this very fertile field of the interaction between uric acid and prostaglandins. Detecting the uric acid may has a potential prompting effect on predicting the renal hemodynamic.