Cheng Lan, Chen Hui, Maboh R Nfornah, Wang Huan
Shengli Clinical Medical College of Fujian Medical University, Fuzhou, China.
Department of Cardiovascular Medicine, Ningbo No.2 Hospital, Ningbo, China.
Kidney Blood Press Res. 2025;50(1):46-60. doi: 10.1159/000542828. Epub 2024 Dec 2.
Our recent findings revealed that CACNA1D D307G mutation participates in the early-onset hypertension.
We used the CRISPR/Cas9 technique to generate the Cacna1d D307G mutation rat model and investigated the effects of Cacna1d D307G mutation on blood pressure (BP) and renal function. Rats fed normal-salt diet had normal plasma aldosterone levels but higher plasma ET-1 and mildly elevated systolic BP (SBP) in D307G and G307G rats compared with the wild type (WT) until 24 weeks. Renal function and renal histopathology did not significantly differ among the three groups.
When fed high-salt diet (HSD), D307G and G307G rats showed more sensitivity to HSD. The results showed a further increase in SBP than in WT rats. Plasma and vascular endothelin-1 (ET-1) level and cortex and renal artery endothelin type A (ETA) receptor protein expression were significantly increased. Enhanced renal injury was also noted as indicated by an increased ratio of kidney weight/body weight, elevated urinary protein and albumin/creatinine ratio, higher kidney injury molecule-1 (KIM-1) levels, advanced fibrosis and apoptosis, and inflammation. Further experiments revealed a reduction in urinary sodium excretion and creatinine clearance. Higher protein expression of renal cortex epithelial sodium channel α subunit (αENaC) was confirmed in D307G and G307G rats fed HSD. However, a selective ETA receptor blockade (ABT-627) could partially reverse the increased SBP, increased serum KIM-1 level, upregulated renal cortex protein expression of αENaC, and reduced urinary sodium excretion with reduced creatinine clearance in D307G rats fed HSD.
Activation of the ET-1/ETA system in D307G mutation rats might have contributed to increased sensitivity to salt loading, augmented hypertension, and exacerbated the renal injury.
我们最近的研究结果表明，CACNA1D基因的D307G突变参与早发性高血压的发生。
我们利用CRISPR/Cas9技术构建了Cacna1d基因D307G突变大鼠模型，并研究了Cacna1d基因D307G突变对血压（BP）和肾功能的影响。喂食正常盐饮食的大鼠血浆醛固酮水平正常，但与野生型（WT）相比，D307G和G307G大鼠的血浆内皮素-1（ET-1）水平更高，收缩压（SBP）轻度升高，这种情况一直持续到24周。三组之间的肾功能和肾脏组织病理学没有显著差异。
当喂食高盐饮食（HSD）时，D307G和G307G大鼠对高盐饮食表现出更高的敏感性。结果显示，它们的收缩压比野生型大鼠进一步升高。血浆和血管内皮素-1（ET-1）水平以及皮质和肾动脉内皮素A型（ETA）受体蛋白表达显著增加。肾脏损伤也有所加重，表现为肾脏重量/体重比增加、尿蛋白和白蛋白/肌酐比值升高、肾脏损伤分子-1（KIM-1）水平升高、纤维化和细胞凋亡进展以及炎症反应。进一步的实验显示尿钠排泄和肌酐清除率降低。喂食高盐饮食的D307G和G307G大鼠肾皮质上皮钠通道α亚基（αENaC）的蛋白表达更高。然而，选择性ETA受体阻滞剂（ABT-627）可以部分逆转喂食高盐饮食的D307G大鼠收缩压升高、血清KIM-1水平升高、肾皮质αENaC蛋白表达上调、尿钠排泄减少以及肌酐清除率降低的情况。
D307G突变大鼠中ET-1/ETA系统的激活可能导致对盐负荷的敏感性增加、高血压加剧以及肾脏损伤加重。
