TRPV4功能异常致肥胖相关性盐敏感高血压的机制

Obesity and high salt intake are two major risk factors of hypertension, but how obesity increases the sensitivity of organism to high salt loading remains elusive. Our previous study revealed that high salt intake elevated sodium content in adipose tissue and interstitial osmotic pressure, which activated PPARδ/adiponectin/SGLT2 to counteract the promotional effect of high salt on hypertension（Cell Metab,2016）.Transient receptor potential vanilloid 4 (TRPV4) is a critical sensor and modulator of osmotic pressure in organism. We have observed that activation of TRPV4 inhibited salt-sensitive hypertension, and its expression was reduced in obese mice. However, whether obesity exacerbates high salt-induced hypertension through repressing TRPV4, which leads to the insensitivity to high osmotic pressure and elevated sodium content in specific tissues, and the underlying mechanism still need to be clarified. Thus, we plan to use three types of knockout mice and perform cellular experiments to clarify the following scientific hypothesis that obesity would reduce the salt sensitivity of organism through repressing TRPV4 to increase the adipose sodium content, and exacerbate the promotional effect of high salt on hypertension by reduction of the compensated activation of adipose PPARδ. On the opposite side, activation of TRPV4 would reverse the above-mentioned process to antagonize the promotional effect of obesity on salt-sensitive hypertension. This study will update the knowledge on how obesity promotes salt-sensitive hypertension and provide new intervention targets to the prevention and cure of hypertension.

肥胖与高盐均是导致高血压的重要危险因素，肥胖可增加盐敏感性加重高血压，但其机制不明。我们前期工作揭示高盐摄入增加脂肪组织钠含量、上调PPARδ及升高组织渗透压，激活肾脏PPARδ/脂联素/SGLT2轴能抑制高盐诱导的高血压（Cell Metab, 2016）。TRPV4是重要的感知及调节渗透压的瞬时受体电位通道，我们发现激活TRPV4能拮抗盐敏感性高血压，而肥胖时TRPV4和PPARδ功能受损，但TRPV4异常如何改变脂肪组织渗透压及导致高血压，PPARδ与其有何内在关联并不清楚。为此，我们提出假设并证实：肥胖致TRPV4功能异常，降低对高盐诱导的高渗透压感知，使脂肪组织渗透压增高和钠潴留，抑制高盐激PPARδ，促进脂肪炎症因子分泌及血管炎症，导致盐敏感性高血压，而激活TRPV4可拮抗肥胖相关性高血压的盐敏感性。本研究拟揭示肥胖促进盐敏感性增加的机制，为盐敏感性高血压的治疗提供新靶点。

TRPV4是重要的感知及调节渗透压的瞬时受体电位通道，我们发现激活TRPV4能拮抗盐敏感性高血压，而肥胖时TRPV4功能受损，但TRPV4异常如何改变脂肪组织渗透压及导致高血压，内在机制并不清楚。为此，我们以高盐导致脂肪TRPV4介导的渗透压感知障碍，进一步促进脂肪炎症因子分泌及血管炎症的机制为核心，以TRPV4-/-小鼠为研究对象，在整体、组织及细胞水平进行研究，并在高血压肥胖人群中进行临床验证及探讨，取得研究成果如下：. 1）高盐导致肥胖性高血压更为显著，高盐导致脂肪细胞中 TRPV4 及 PPARδ 的表达上调，且与渗透压相关：相同高盐膳食条件下，TRPV4敲除小鼠血压较野生小鼠血压升高。且高盐可通过介导细胞内Ca2+和Na+来影响脂肪细胞的功能，进而影响脂肪细胞分泌脂联素（adiponectin）的水平。. 2）TRPV4通过介导脂联素和抑制氧化应激来引起血压水平的下降：TRPV4激动剂芹菜素喂养小鼠，脂联素和抗氧化酶（SOD1,Gpx1）的表达均升高，在TRPV4敲除小鼠中，脂联素分泌水平和表达以及抗氧化酶的表达水平显著下降，明确了TRPV4可能通过介导脂联素和抑制氧化应激来引起血压水平的下降。. 3）TRPV4敲除小鼠中，脂肪组织Nrf2和AKT的表达水平均下降，进一步说明TRPV4可能通过TRPV4/AKT/Nrf2/adiponectin的通路来调节肥胖小鼠的血压。. 4）在临床肥胖高血压人群中，初步探讨了炎症反应对肥胖患者脂肪和血管细胞的影响及其对代谢手术减脂后的改善效应。. 本研究揭示了肥胖促进盐敏感性增加的机制，发现TRPV4可能是盐敏感性高血压治疗的新靶点。