最新的研究表明果糖诱发盐敏感性高血压与肾脏髓袢（TAL）的钠钾氯共转运体NKCC2的活化有关。我们的预实验结果显示肾素原受体( (pro)renin receptor，PRR)介导了果糖诱导的NKCC2的活化及盐敏感性的增强，高果糖上调肾脏PRR及尿液可溶性PRR的水平，并伴随肾内RAS及NKCC2的活化，运用PRR抑制多肽PRO20有效地抑制了果糖诱导的肾内RAS及NKCC2的活化及盐敏感性高血压，外源性尿酸能刺激肾脏PRR的表达。因此，我们假设果糖通过尿酸刺激肾脏PRR的表达，进而活化NKCC2，从而增强盐敏感性。为验证这一假说，本项目利用别嘌呤醇抑制内源性尿酸的产生、TAL PRR特异性敲除小鼠和呋塞米以及体外实验，明确TAL PRR在果糖诱导的盐敏性高血压中的作用及分子机制，将为果糖诱导的盐敏感性高血压的发生机制及干预靶点提供新的视点。

During the past several decades, there has been a dramatic increase in fructose consumption worldwide in parallel with epidemics of metabolic diseases. The American Heart Association has recently released new recommendations to reduce the dietary intake of added sugars. A large body of evidence has established a link between fructose intake and hypertension. Recent evidence demonstrates that fructose load induces salt-sensitive hypertension associated with activation of Na-K-Cl cotransporter (NKCC2), a major ion transporter in the thick ascending limb (TAL). However, it remains elusive as to how fructose regulates NKCC2. Our preliminary studies provided compelling evidence supporting a role of (pro)renin receptor (PRR) in mediating fructose-induced NKCC2 activation and hence the increased salt sensitivity. In particular, we presented evidence that fructose loading in rats elevated renal and urinary soluble PRR and renal PRR mRNA expression along with indices of activation of intrarenal renin-angiotensin system (RAS) and NKCC2. Pharmacological studies demonstrated that administration of a PRR decoy inhibitor PRO20 effectively suppressed intrarenal RAS and NKCC2 and abolished salt-sensitive hypertension. Moreover, we discovered that administration of exogenous uric acid, a metabolic product of fructose, stimulated renal PRR expression. Based on these observations, we hypothesize that fructose via uric acid stimulates renal PRR leading to activation of NKCC2, ultimately increasing salt sensitivity. To test this hypothesis, we propose the following 4 specific aims: 1) to test the effect of inhibition of endogenous generation of uric acid with allopurinol on renal PRR expression and fructose/salt-induced hypertension, 2) to examine the blood pressure phenotype in TAL-specific PRR knockout mice, 3) to examine the effect of furosemide on fructose/salt-induced hypertension, and 4) to conduct in vitro experiments to define PRR as direct regulator of NKCC2. Overall, new information resulted from this proposal is expected to offer new insight into the role of PRR and intrarenal RAS in fructose-induced salt-sensitive hypertension.