原发性醛固酮增多症动物模型研究进展

Advances in animal models of primary aldosteronism

摘要

原发性醛固酮增多症（PA）是继发性高血压的重要类型，其发病机制涉及离子通道异常与肾上腺类固醇合成调控的复杂交互。动物模型是解析其致病机制的重要工具。本文从机制导向整合角度综述了常用 PA 动物模型，比较遗传修饰模型与功能性模型在“膜去极化-钙信号-醛固酮合成酶（CYP11B2）激活”通路中的作用特点及其在模拟人类表型方面的差异。总体而言，遗传模型有助于阐明分子机制，而功能性模型更接近持续性醛固酮增多状态。然而，现有模型在器官特异性及表型一致性方面仍存在局限。未来应加强模型整合与分层应用，并结合多组学技术，以提升 PA 机制研究的转化应用价值。

Abstract

Primary aldosteronism (PA) is a major cause of secondary hypertension, characterized by complex interactions between ion channel dysfunction and adrenal steroidogenesis. Animal models are essential for elucidating its underlying mechanisms. This review provides a mechanism-oriented synthesis of commonly used PA models, comparing genetically modified and functional models in terms of their roles in the “membrane depolarization-calcium signaling-CYP11B2 activation” axis and their ability to recapitulate human phenotypes. Overall, genetic models are useful in dissecting molecular mechanisms, whereas functional models more closely mimic sustained aldosterone excess observed in clinical settings. However, current models remain limited by insufficient organ specificity and phenotypic consistency. Future efforts should focus on integrative and stratified model application, combined with emerging multi-omics approaches to advance mechanistic insights and improve translational applicability in PA.

关键词

原发性醛固酮增多症 / 动物模型 / 离子通道 / 醛固酮

Key words

primary aldosteronism / animal models / ion channels / aldosterone

参考文献

[1] Davies LA, Hu C, Guagliardo NA, et al. Task channel deletion in mice causes primary hyperaldosteronism[J]. Proc Natl Acad Sci U S A, 2008, 105(6): 2203-2208.

[2] Chen AX, Nishimoto K, Nanba K, et al. Potassium channels related to primary aldosteronism: expression similarities and differences between human and rat adrenals[J]. Mol Cell Endocrinol, 2015, 417: 141-148.

[3] Heitzmann D, Derand R, Jungbauer S, et al. Invalidation of TASK1 potassium channels disrupts adrenal gland zonation and mineralocorticoid homeostasis[J]. EMBO J, 2008, 27(1): 179-187.

[4] Guagliardo NA, Yao J, Hu C, et al. TASK—3 channel deletion in mice recapitulates low—renin essential hypertension[J]. Hypertension, 2012, 59(5): 999-1005.

[5] Guagliardo NA, Yao J, Stipes EJ, et al. Adrenal tissue—specific deletion of TASK channels causes aldosterone—driven angiotensin Ⅱ—independent hypertension[J]. Hypertension, 2019, 73(2): 407-414.

[6] Nogueira EF, Gerry D, Mantero F, et al. The role of TASK1 in aldosterone production and its expression in normal adrenal and aldosterone—producing adenomas[J]. Clin Endocrinol (Oxf), 2010, 73(1): 22-29.

[7] Gomez—Sanchez CE, Oki K . Minireview: potassium channels and aldosterone dysregulation: is primary aldosteronism a potassium channelopathy?[J]. Endocrinology, 2014, 155(1): 47-55.

[8] Bandulik S, Tauber P, Penton D, et al. Severe hyperaldosteronism in neonatal TASK3 potassium channel knockout mice is associated with activation of the intraadrenal renin—angiotensin system[J]. Endocrinology, 2013, 154(8): 2712-2722.

[9] Wang Z, Zhao X, Bu L, et al. Low sodium intake ameliorates hypertension and left ventricular hypertrophy in mice with primary aldosteronism[J]. Front. Physiol, 2023, 14: 1136574.

[10] Shi L, Yuan F, Wang X, et al. Mineralocorticoid receptor—dependent impairment of baroreflex contributes to hypertension in a mouse model of primary aldosteronism[J]. Front Physiol, 2019, 10: 1434.

[11] Gancayco CA, Gerding MR, Breault DT, et al. Intrinsic adrenal TWIK—related acid—sensitive TASK channel dysfunction produces spontaneous calcium oscillations sufficient to drive AngⅡ (angiotensin Ⅱ)—unresponsive hyperaldosteronism[J]. Hypertension, 2022, 79(11): 2552-2564.

[12] Aragao—Santiago L, Gomez—Sanchez CE, Mulatero P, et al. Mouse models of primary aldosteronism: from physiology to pathophysiology[J]. Endocrinology, 2017, 158(12): 4129-4138.

[13] Grimm PR, Irsik DL, Settles DC, et al. Hypertension of Kcnmb1^−/− is linked to deficient K⁺ secretion and aldosteronism [J]. Proc Natl Acad Sci U S A, 2009, 106(28): 11800-11805.

[14] Sausbier M, Arntz C, Bucurenciu I, et al. Elevated blood pressure linked to primary hyperaldosteronism and impaired vasodilation in BK channel—deficient mice[J]. Circulation, 2005, 112(1): 60-68.

[15] Xiao J, Cheng X, Huang D, et al. KCNE gene family: from basic functions to diseases[J]. Genes Dis, 2025, 13(4): 101918.

[16] Arrighi I, Bloch—Faure M, Grahammer F, et al. Altered potassium balance and aldosterone secretion in a mouse model of human congenital long QT syndrome[J]. Proc Natl Acad Sci U S A, 2001, 98(15): 8792-8797.

[17] Göppner C, Orozco IJ, Hoegg—Beiler MB, et al. Pathogenesis of hypertension in a mouse model for human CLCN2 related hyperaldosteronism[J]. Nat Commun, 2019, 10: 4678.

[18] Schewe J, Seidel E, Forslund S, et al. Elevated aldosterone and blood pressure in a mouse model of familial hyperaldosteronism with ClC—2 mutation[J]. Nat Commun, 2019, 10: 5155.

[19] Niehrs C . Function and biological roles of the Dickkopf family of Wnt modulators[J]. Oncogene, 2006, 25(57): 7469-7481.

[20] El Wakil A, Bandulik S, Guy N, et al. Dkk3 is a component of the genetic circuitry regulating aldosterone biosynthesis in the adrenal cortex[J]. Hum Mol Genet, 2012, 21(22): 4922-4929.

[21] Berthon A, Sahut—Barnola I, Lambert—Langlais S, et al. Constitutive β—catenin activation induces adrenal hyperplasia and promotes adrenal cancer development[J]. Hum Mol Genet, 2010, 19(8): 1561-1576.

[22] Berber M, Leng S, Wengi A, et al. Calcineurin regulates aldosterone production via dephosphorylation of NFATC4[J]. JCI Insight, 2023, 8(14): e157027.

[23] Forlino A, Piazza R, Tiveron C, et al. A diastrophic dysplasia sulfate transporter (SLC26A2) mutant mouse: morphological and biochemical characterization of the resulting chondrodysplasia phenotype[J]. Hum Mol Genet, 2005, 14(6): 859-871.

[24] Spyroglou A, Bozoglu T, Rawal R, et al. Diastrophic dysplasia sulfate transporter (SLC26A2) is expressed in the adrenal cortex and regulates aldosterone secretion[J]. Hypertension, 2014, 63(5): 1102-1109.

[25] Kakoki M, Pochynyuk OM, Hathaway CM, et al. Primary aldosteronism and impaired natriuresis in mice underexpressing TGFβ1[J]. Proc Natl Acad Sci U S A, 2013, 110(14): 5600-5605.

[26] Bhandaru M, Kempe DS, Rotte A, et al. Hyperaldosteronism, hypervolemia, and increased blood pressure in mice expressing defective APC[J]. Am J Physiol Regul Integr Comp Physiol, 2009, 297(3): R571-575.

[27] Makhanova N, Hagaman J, Kim HS, et al. Salt—sensitive blood pressure in mice with increased expression of aldosterone synthase[J]. Hypertension, 2008, 51(1): 134-140.

[28] Gu H, Ma Z, Wang J, et al. Salt—dependent blood pressure in human aldosterone synthase—transgenic mice[J]. Sci Rep, 2017, 7: 492.

[29] Wall SM, Lazo—Fernandez Y . The role of pendrin in renal physiology[J]. Annu Rev Physiol, 2015, 77: 363-378.

[30] Xu N, Hirohama D, Ishizawa K, et al. Hypokalemia and pendrin induction by aldosterone[J]. Hypertension, 2017, 69(5): 855-862.

[31] Shibata S. Role of pendrin in the pathophysiology of aldosterone—induced hypertension[J]. Am J Hypertens, 2019, 32(7): 607-613.

[32] Azibani F, Devaux Y, Coutance G, et al. Aldosterone inhibits the fetal program and increases hypertrophy in the heart of hypertensive mice[J]. PLoS ONE, 2012, 7(5): e38197.

[33] Doi M, Takahashi Y, Komatsu R, et al. Salt—sensitive hypertension in circadian clock—deficient Cry—null mice involves dysregulated adrenal Hsd3b6[J]. Nat Med, 2010, 16(1): 67-74.

[34] van Rooyen D, Lerario AM, Little DW, et al. Chronic activation of adrenal Gq signaling induces Cyp11b2 expression in the zona fasciculata and hyperaldosteronism[J]. Mol Cell Endocrinol, 2024, 585: 112176.

[35] 马鑫, 王超, 欧阳金芝, 等 . 原发性醛固酮增多症大鼠模型的建立[J]. 中华实验外科杂志, 2009, 26(6): 791-793.

[36] Peng KY, Chang HM, Lin YF, et al. miRNA—203 modulates aldosterone levels and cell proliferation by targeting Wnt5a in aldosterone—producing adenomas[J]. J Clin Endocrinol Metab, 2018, 103(10): 3737-3747.

[37] Sedlack AJH, Hatfield SJ, Kumar S, et al. Preclinical models of adrenocortical cancer[J]. Cancers, 2023, 15(11): 2873.

[38] Zhang XZ, Mou TT, Wang YX, et al. Establishment and evaluation of a patient—derived organoids—based xenograft model of primary aldosteronism using¹⁸F—AlF—NOTA—pentixather PET/CT: bridging preclinical and clinical imaging [J]. J Transl Med, 2025, 23: 927.

[39] Timmerman SA, Mullen N, Taylor AE, et al. Characterization of a biochemical mouse model of primary aldosteronism for thermal therapies[J]. bioRxiv[Preprint], 2024: 2024.05.07.592955.

[40] Perez—Rivas LG, Rhayem Y, Sabrautzki S, et al. Genetic characterization of a mouse line with primary aldosteronism[J]. J Mol Endocrinol, 2017, 58(2): 67-78.

[41] Stölting G, Dinh HA, Volkert M, et al. Isradipine therapy in Cacna1dIle772Met/+ mice ameliorates primary aldosteronism and neurologic abnormalities[J]. JCI Insight, 2023, 8(20): e162468.

[42] You M, Lu Z, Wang B, et al. Meriones unguiculatus serves as a spontaneous primary aldosteronism rodent model[J]. PLoS One, 2025, 20(2): e0314943.

基金资助

甘肃省科技厅青年科技基金计划(23JRRA1642)

萃英科技创新计划面上项目(CY2023-MS-B02)

兰州大学教育教学改革研究项目(DELC-202303)

萃英学子科研培育计划(CYXZ2023-40)

甘肃省卫生行业项目(GSWSKY2020-25)