Verzicco Ignazio, Tedeschi Stefano, Graiani Gallia, Bongrani Alice, Carnevali Maria Luisa, Dancelli Simona, Zappa Jessica, Mattei Silvia, Bovino Achiropita, Cavazzini Stefania, Rocco Rossana, Calvi Anna, Palladini Barbara, Volpi Riccardo, Cannone Valentina, Coghi Pietro, Borghetti Alberico, Cabassi Aderville
Cardiorenal and Hypertension Research Unit, Physiopathology Unit, Clinica Medica Generale e Terapia Medica, Department of Medicine and Surgery (DIMEC), University of Parma, Parma, Italy.
Histology and Histopathology Unit and Molecular Biology Laboratory, Dental School Parma, University of Parma, Parma, Italy.
Front Cardiovasc Med. 2022 Jun 1;9:897244. doi: 10.3389/fcvm.2022.897244. eCollection 2022.
In addition to long-term regulation of blood pressure (BP), in the kidney resides the initial trigger for hypertension development due to an altered capacity to excrete sodium and water. Betaine is one of the major organic osmolytes, and its betaine/gamma-aminobutyric acid transporter (BGT-1) expression in the renal medulla relates to interstitial tonicity and urinary osmolality and volume. This study investigated altered water and sodium balance as well as changes in antidiuretic hormone (ADH) activity in female spontaneously hypertensive (SHR) and normotensive Wistar Kyoto (WKY) rats from their 3-5 weeks of age (prehypertensive phase) to SHR's 28-30 weeks of age (established hypertension-organ damage). Young prehypertensive SHRs showed a reduced daily urine output, an elevated urine osmolarity, and higher immunostaining of tubule BGT-1, alpha-1-Na-K ATPase in the outer medulla vs. age-matched WKY. ADH circulating levels were not different between young prehypertensive SHR and WKY, but the urine aquaporin2 (AQP2)/creatinine ratio and labeling of AQP2 in the collecting duct were increased. At 28-30 weeks, hypertensive SHR with moderate renal failure did not show any difference in urinary osmolarity, urine AQP2/creatinine ratio, tubule BGT-1, and alpha-1-Na-K ATPase as compared with WKY. These results suggest an increased sensitivity to ADH in prehypertensive female SHR. On this basis, a second series of experiments were set to study the role of ADH V1 and V2 receptors in the development of hypertension, and a group of female prehypertensive SHRs were treated from the 25th to 49th day of age with either V1 (OPC21268) or V2 (OPC 41061) receptor antagonists to evaluate the BP time course. OPC 41061-treated SHRs had a delayed development of hypertension for 5 weeks without effect in OPC 21268-treated SHRs. In prehypertensive female SHR, an increased renal ADH sensitivity is crucial for the development of hypertension by favoring a positive water balance. Early treatment with selective V2 antagonism delays future hypertension development in young SHRs.
除了对血压（BP）的长期调节外，肾脏还存在因钠和水排泄能力改变而引发高血压的初始因素。甜菜碱是主要的有机渗透溶质之一，其在肾髓质中的甜菜碱/γ-氨基丁酸转运体（BGT-1）表达与间质张力、尿渗透压和尿量有关。本研究调查了雌性自发性高血压（SHR）大鼠和正常血压的Wistar Kyoto（WKY）大鼠从3至5周龄（高血压前期）到SHR的28至30周龄（已确诊高血压-器官损伤）期间水和钠平衡的变化以及抗利尿激素（ADH）活性的改变。年轻的高血压前期SHR与年龄匹配的WKY相比，每日尿量减少、尿渗透压升高，外髓质肾小管BGT-1、α-1-Na-K ATP酶的免疫染色更高。年轻的高血压前期SHR和WKY之间循环中的ADH水平没有差异，但集合管中尿水通道蛋白2（AQP2）/肌酐比值和AQP2标记增加。在28至30周时，患有中度肾衰竭的高血压SHR与WKY相比，尿渗透压、尿AQP2/肌酐比值、肾小管BGT-1和α-1-Na-K ATP酶没有任何差异。这些结果表明高血压前期雌性SHR对ADH的敏感性增加。在此基础上，进行了第二系列实验以研究ADH V1和V2受体在高血压发展中的作用，一组高血压前期雌性SHR在25至49日龄期间用V1（OPC21268）或V2（OPC 41061）受体拮抗剂治疗以评估血压随时间的变化过程。用OPC 41061治疗的SHR高血压发展延迟了5周，而用OPC 21268治疗的SHR则没有效果。在高血压前期雌性SHR中，肾脏对ADH敏感性增加通过促进正水平衡对高血压发展至关重要。早期用选择性V2拮抗剂治疗可延迟年轻SHR未来高血压的发展。
