Animal models of hypertension and concurrent organs injury

Ye Wang , Xiaoliang Jiang , Zhiwei Yang

Animal Models and Experimental Medicine ›› 2025, Vol. 8 ›› Issue (10) : 1775 -1784.

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Animal Models and Experimental Medicine ›› 2025, Vol. 8 ›› Issue (10) :1775 -1784. DOI: 10.1002/ame2.70089
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Animal models of hypertension and concurrent organs injury
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Abstract

Although hypertension is a frequently seen chronic condition across the world, its exact cause remains unclear. Animal models are beneficial for clarifying the pathogenic mechanism of hypertension and examining new treatments. An optimal animal model for studies on hypertension must well mimic human-like hemodynamics and pathophysiological structural modification, showing human disease features and complications timely or even ahead of time. A review of the most frequently used hypertensive animal models available, including small and large animals, induced and genetic models, would provide an insight into the appropriate targets to be addressed in the development of different hypertensive animal models. Another focus of the review are the processes of target-organs injury caused by high blood pressure, which mainly influences human health.

Keywords

animal / genetic model / hypertension / organ damage

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Ye Wang, Xiaoliang Jiang, Zhiwei Yang. Animal models of hypertension and concurrent organs injury. Animal Models and Experimental Medicine, 2025, 8(10): 1775-1784 DOI:10.1002/ame2.70089

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References

[1]

Zhou B, Perel P, Mensah GA, Ezzati M. Global epidemiology, health burden and effective interventions for elevated blood pressure and hypertension. Nat Rev Cardiol. 2021;18(11):785-802.

[2]

Joseph G, Thanh Pham V, Kragh Andersen P, et al. Cardiovascular events according to blood pressure thresholds recommended by ACC/AHA. Blood Press. 2024;33(1):2380346.

[3]

Olsen MH, Angell SY, Asma S, et al. A call to action and a lifecourse strategy to address the global burden of raised blood pressure on current and future generations: the lancet commission on hypertension. Lancet Lond Engl. 2016;388(10060):2665-2669.

[4]

Wang Z, Chen Z, Zhang L, et al. Status of hypertension in China: results from the China hypertension survey, 2012–2015. Circulation. 2018;137(22):2344-2356.

[5]

Vlachovsky SG, Azurmendi PJ, Oddo EM, et al. High sodium, rather than high blood pressure, induces immune cell activation and renal infiltration in ovariectomized adult Wistar rats. Biochem Biophys Res Commun. 2024;722:150147.

[6]

Pitzer A, Elijovich F, Laffer CL, et al. DC ENaC-dependent inflammasome activation contributes to salt-sensitive hypertension. Circ Res. 2022;131:328-344.

[7]

Barbaro NR, Foss JD, Kryshtal DO, et al. Dendritic cell amiloride-sensitive channels mediate sodium-induced inflammation and hypertension. Cell Rep. 2017;21:1009-1020.

[8]

Sahinoz M, Elijovich F, Ertuglu LA, et al. Salt sensitivity of blood pressure in blacks and women: a role of inflammation, oxidative stress, and epithelial Na(+) channel. Antioxid Redox Signal. 2021;35:1477-1493.

[9]

Ruggeri Barbaro N, Van Beusecum J, Xiao L, et al. Sodium activates human monocytes via the NADPH oxidase and isolevuglandin formation. Cardiovasc Res. 2021;117:1358-1371.

[10]

Mattson DL. Infiltrating immune cells in the kidney in salt-sensitive hypertension and renal injury. Am J Physiol Renal Physiol. 2014;307:F499-F508.

[11]

Kirabo A, Fontana V, de Faria AP, et al. DC isoketal-modified proteins activate T cells and promote hypertension. J Clin Invest. 2014;124:4642-4656.

[12]

Khanna AK, Maheshwari K, Mao G, et al. Association between mean arterial pressure and acute kidney injury and a composite of myocardial injury and mortality in postoperative critically ill patients: a retrospective cohort analysis. Crit Care Med. 2019;47(7):910-917.

[13]

Boucherat O, Agrawal V, Lawrie A, Bonnet S. The latest in animal models of pulmonary hypertension and right ventricular failure. Circ Res. 2022;130(9):1466-1486.

[14]

Lerman LO, Kurtz TW, Touyz RM, et al. Animal models of hypertension: a scientific statement from the American Heart Association. Hypertension. 2019;73(6):e87-e120.

[15]

Wang L, Tang T, Tian X, Peng C, Wu S. Animal models of pulmonary arterial hypertension associated with atrial septal defect. Sci Rep. 2024;14(1):18287.

[16]

Zhang J, He J, Liao Y, Xia X, Yang F. Genetic association between gut microbiome and blood pressure and blood cell count as mediator: a two-step Mendelian randomization analysis. Gene. 2024;925:148573.

[17]

Buneeva OA, Fedchenko VI, Kaloshina SA, Zavyalova MG, Zgoda VG, Medvedev AE. Comparative proteomic analysis of renal tissue of normotensive and hypertensive rats. Biomed Khim. 2024;70(2):89-98.

[18]

Abais-Battad JM, Saravia FL, Lund H, et al. Dietary influences on the dahl SS rat gut microbiota and its effects on salt-sensitive hypertension and renal damage. Acta Physiol. 2021;232:e13662.

[19]

Cansu , Korkmaz C. Pulmonary hypertension in connective tissue diseases: epidemiology, pathogenesis, and treatment. Clin Rheumatol. 2023;42(10):2601-2610.

[20]

Tang H, Gupta A, Morrisroe SA, et al. Deficiency of the Deubiquitinase UCHL1 attenuates pulmonary arterial hypertension. Circulation. 2024;150(4):302-316.

[21]

Pereyra EV, Godoy Coto J, Velez Rueda JO, et al. Beneficial consequences of one-month Oral treatment with cannabis oil on cardiac hypertrophy and the mitochondrial Pool in spontaneously hypertensive rats. Cannabis Cannabinoid Res. 2024;13.

[22]

You R, Jia Z. Pathophysiological role of Na-Cl cotransporter in kidneys, blood pressure, and metabolism. Hum Cell. 2024;37(5):1306-1315.

[23]

Ben-Shabat M, Awad-Igbaria Y, Sela S, et al. Predisposition to cortical neurodegenerative changes in brains of hypertension prone rats. J Transl Med. 2023;21(1):51.

[24]

Meng P, Liu T, Zhong Z, et al. A novel rat model of cerebral small vessel disease based on vascular risk factors of hypertension, aging, and cerebral hypoperfusion. Hypertens Res. 2024;47(8):2195-2210.

[25]

Wang W, Liu R, Cao G, et al. A reliable rabbit model for hyperkinetic pulmonary hypertension. J Thorac Cardiovasc Surg. 2010;140(2):395-399.

[26]

Rat genome database. 2017;10(17). http://rgd.mcw.edu/rgdweb/search/strains.html?term=hypertensive+rats&obj=strain

[27]

Dasinger JH, Walton SD, Burns EC, et al. Impact of bedding on Dahl salt-sensitive hypertension and renal damage. Am J Physiol Ren Physiol. 2022;323:F666-F672.

[28]

Padmanabhan S, Joe B. Towards precision medicine for hypertension: a review of genomic, epigenomic, and microbiomic effects on blood pressure in experimental rat models and humans. Physiol Rev. 2017;97:1469-1528.

[29]

Aragane Y, Higashino T, Kinoshita K, Ashenagar MS, Higashino H. Hypertension-associated genes in the mesenteric artery of three spontaneously hypertensive rat substrains identified using a DNA Array method. Front Biosci (Landmark ed). 2022;27(6):191.

[30]

Kitchener JB. Dr. Lewis Kitchener dahl, the dahl rats, and the “inconvenient truth” about the genetics of hypertension. Hypertension. 2015;65:963-969.

[31]

Jiang X, Liu X, Liu X, et al. Low-dose aspirin treatment attenuates male rat salt-sensitive hypertension via platelet cyclooxygenase 1 and complement Cascade pathway. J Am Heart Assoc. 2020;9(1):e013470.

[32]

Grano de Oro A, Kumariya S, Mell B, Zubcevic J, Joe B, Osman I. Spontaneous vascular dysfunction in dahl salt-sensitive male rats raised without a high-salt diet. Physiol Rep. 2024;12(14):e16165.

[33]

Bongartz LG, Braam B, Gaillard CA, et al. Target organ cross talk in cardiorenal syndrome: animal models. Am J Physiol Ren Physiol. 2012;303:F1253-F1263.

[34]

Ge Y, Fan F, Didion SP, Roman RJ. Impaired myogenic response of the afferent arteriole contributes to the increased susceptibility to renal disease in Milan normotensive rats. Physiol Rep. 2017;5:e13089.

[35]

Ware K, Yildiz V, Xiao M, et al. Hypertension and the kidney: reduced kidney mass is bad for both normotensive and hypertensive rats. Am J Hypertens. 2021;34(11):1196-1202.

[36]

Yamaguchi S, Matsumoto K, Wang W, Nakamura K. Differential antihypertensive effects of Oral doses of acetylcholine between spontaneously hypertensive rats and normotensive rats. Foods. 2021;10(9):2107.

[37]

Ma MCJ, Pettus JM, Jakoubek JA, et al. Contribution of independent and pleiotropic genetic effects in the metabolic syndrome in a hypertensive rat. PLoS One. 2017;12:e0182650.

[38]

Guy R, Volkman R, Wilczynski E, et al. A novel rodent model of hypertensive cerebral small vessel disease with white matter hyperintensities and peripheral oxidative stress. Int J Mol Sci. 2022;23(11):5915.

[39]

Ferrario CM, Groban L, Wang H, et al. The renin-angiotensin system biomolecular cascade: a 2022 update of newer insights and concepts. Kidney Int Suppl. 2022;12(1):36-47.

[40]

Mir SA, Zhang K, Milic M, et al. Analysis and validation of traits associated with a single nucleotide polymorphism Gly364Ser in catestatin using humanized chromogranin A mouse models. J Hypertens. 2016;34:68-78.

[41]

Elijovich F, Weinberger MH, Anderson CA, et al. salt sensitivity of blood pressure: a scientific statement from the American Heart Association. Hypertension. 2016;68:e7-e46.

[42]

Chowdhury JA, Liu CH, Zuber AM, O'Shaughnessy KM. An inducible transgenic mouse model for familial hypertension with hyperkalaemia (Gordon's syndrome or pseudohypoaldosteronism type II). Clin Sci (Lond). 2013;124:701-708.

[43]

Ronzaud C, Loffing-Cueni D, Hausel P, et al. Renal tubular NEDD4–2 deficiency causes NCC-mediated salt-dependent hypertension. J Clin Invest. 2013;123:657-665.

[44]

Crowley SD, Frey CW, Gould SK, et al. Stimulation of lymphocyte responses by angiotensin II promotes kidney injury in hypertension. Am J Physiol Renal Physiol. 2008;295:F515-F524.

[45]

Baumann D, Van Helden D, Evans LC, Vulchanova L, Dayton A, Osborn JW. IL-1R mediated activation of renal sensory nerves in DOCA-salt hypertension. Hypertension. 2024;81(8):1811-1821.

[46]

Dunaway LS, Saii K, LoBue A, et al. The hemodynamic response to nitrite is acute and dependent upon tissue perfusion. Nitric Oxide. 2024;150:47-52.

[47]

Chen S, Xie JD, Xie MT, et al. Przewaquinone A inhibits angiotensin II-induced endothelial diastolic dysfunction activation of AMPK. Phytomedicine. 2024;133:155885.

[48]

Wain LV, Verwoert GC, O'Reilly PF. Genome-wide association study identifies six new loci influencing pulse pressure and mean arterial pressure. Nat Genet. 2011;43:1005-1011.

[49]

Newton-Cheh C, Johnson T, Gateva V. Genome-wide association study identifies eight loci associated with blood pressure. Nat Genet. 2009;41:666-676.

[50]

Levy D, Ehret GB, Rice K. Genome-wide association study of blood pressure and hypertension. Nat Genet. 2009;41:677-687.

[51]

Yang Z, Sibley DR, Jose PA. D5 dopamine receptor knockout mice and hypertension. J Recept Signal Transduct Res. 2004;24(3):149-164.

[52]

Zhang Y, Cuevas S, Asico LD, et al. Deficient dopamine D2 receptor function causes renal inflammation independently of high blood pressure. PLoS One. 2012;7:e38745.

[53]

Fung MM, Rana BK, Tang CM, et al. Dopamine D1 receptor (DRD1) genetic polymorphism: pleiotropic effects on heritable renal traits. Kidney Int. 2009;76:1070-1080.

[54]

Padmanabhan S, Menni C, Lee WK, et al. The effects of sex and method of blood pressure measurement on genetic associations with blood pressure in the PAMELA study. J Hypertens. 2010;28:465-477.

[55]

Ji W, Foo JN, O'Roak BJ, et al. Rare independent mutations in renal salt handling genes contribute to blood pressure variation. Nat Genet. 2008;40:592-599.

[56]

Li H, Weatherford ET, Davis DR, et al. Renal proximal tubule angiotensin AT1A receptors regulate blood pressure. Am J Physiol Regul Integr Comp Physiol. 2011;301:R1067-R1077.

[57]

Michell AR, Debnam ES, Unwin RJ. Regulation of renal function by the gastrointestinal tract: potential role of gut-derived peptides and hormones. Annu Rev Physiol. 2008;70:379-403.

[58]

Furness JB, Rivera LR, Cho HJ, Bravo DM, Callaghan B. The gut as a sensory organ. Nat Rev Gastroenterol Hepatol. 2013;10:729-740.

[59]

Pisegna JR, Tarasova NI, Kopp JA, et al. Postprandial changes in renal function are mediated by elevated serum gastrin acting at cholecystokinin type B receptors (CCKBR) in the kidney (abstract). Gastroenterology. 1996;110:1106A.

[60]

Jiang X, Chen W, Liu X, et al. The synergistic roles of cholecystokinin B and dopamine D5 receptors on the regulation of renal sodium excretion. PLoS One. 2016;11:e0146641.

[61]

Jiang X, Liu Y, Zhang X, et al. Gastrin-SiO2 microspheres ameliorate salt-sensitive hypertension by inhibiting intestinal Na+/H+ exchanger-3 activity through a PKC-mediated NHERF1 and NHERF2 pathway. Hypertension. 2022;79(8):1668-1679.

[62]

Zhang QY, Guo Y, Jiang XL, et al. Intestinal Cckbr-specific knockout mouse as a novel model of salt-sensitive hypertension via sodium over-absorption. J Geriatr Cardiol. 2023;20(7):538-547.

[63]

Chen Y, Asico LD, Zheng S, et al. Gastrin and D1dopamine receptor interact to induce natriuresis and diuresis. Hypertension. 2013;62:927-933.

[64]

Griffin KA. Hypertensive kidney injury and the progression of chronic kidney disease. Hypertension. 2017;70:687-694.

[65]

Griffin KA, Polichnowski A, Litbarg N, Picken M, Venkatachalam MA, Bidani AK. Critical blood pressure threshold dependence of hypertensive injury and repair in a malignant nephrosclerosis model. Hypertension. 2014;64:801-807.

[66]

Iadecola C. The pathobiology of vascular dementia. Neuron. 2013;80:844-866.

[67]

Jama HA, Muralitharan RR, Xu C, et al. Rodent models of hypertension. Br J Pharmacol. 2022;179(5):918-937.

[68]

Larouche-Lebel É, Loughran KA, Oyama MA, et al. Plasma and tissue angiotensin-converting enzyme 2 activity and plasma equilibrium concentrations of angiotensin peptides in dogs with heart disease. J Vet Intern Med. 2019;33(4):1571-1584.

[69]

Hsu CN, Tain YL. Animal models for DOHaD research: focus on hypertension of developmental origins. Biomedicine. 2021;9(6):623.

[70]

Hofstaetter JG, Blouin S, Friehs I, Klaushofer K, Roschger P. No effect of short-term hypertension on bone matrix mineralization in a surgical animal model in immature rabbits. Clin Exp Hypertens. 2012;34:107-112.

[71]

Fossum TW, Baltzer WI, Miller MW, et al. A novel aortic coarctation model for studying hypertension in the pig. J Investig Surg. 2003;16:35-44.

[72]

Rong N, Liu J. Development of animal models for emerging infectious diseases by breaking the barrier of species susceptibility to human pathogens. Emerg Microbes Infect. 2023;12(1):2178242.

[73]

Chade AR, Rodriguez-Porcel M, Grande JP, et al. Distinct renal injury in early atherosclerosis and renovascular disease. Circulation. 2002;106:1165-1171.

[74]

Shi X, Bai Y, Ke Y, et al. Ageing-related aorta remodelling and calcification occur earlier and progress more severely in rats with spontaneous hypertension. Histol Histopathol. 2018;33:727-736.

[75]

Ehret GB, Caulfield MJ. Genes for blood pressure: An opportunity to understand hypertension. Eur Heart J. 2013;34(13):951-961.

[76]

Wang S, Liu H, Yang P, et al. Exploring the genetic association of allergic diseases with cardiovascular diseases: a bidirectional mendelian randomization study. Front Immunol. 2023;14:1175890.

[77]

Guzik TJ, Hoch NE, Brown KA, et al. Role of the T cell in the genesis of angiotensin II induced hypertension and vascular dysfunction. J Exp Med. 2007;204:2449-2460.

[78]

Crowley SD, Zhang J, Herrera M, Griffiths R, Ruiz P, Coffman TM. Role of AT1 receptor-mediated salt retention in angiotensin II-dependent hypertension. Am J Physiol Renal Physiol. 2011;301:F1124-F1130.

[79]

Antunes TT, Callera GE, He Y, et al. Transient receptor potential melastatin 7 cation channel kinase: new player in angiotensin II-induced hypertension. Hypertension. 2016;67:763-773.

[80]

Avendaño MS, García-Redondo AB, Zalba G, et al. mPGES-1 (microsomal prostaglandin E synthase-1) mediates vascular dysfunction in hypertension through oxidative stress. Hypertension. 2018;72:492-502.

[81]

Leloup AJA, De Moudt S, Van Hove CE, et al. Short-term angiotensin II treatment affects large artery biomechanics and function in the absence of small artery alterations in mice. Front Physiol. 2018;9:582.

[82]

Mattson DL, Meister CJ, Marcelle ML. Dietary protein source determines the degree of hypertension and renal disease in the Dahl salt-sensitive rat. Hypertension. 2005;45:736-741.

[83]

Fuchs FD, Whelton PK. High blood pressure and cardiovascular disease. Hypertension. 2020;75(2):285-292.

[84]

Majid DSA, Prieto MC, Castillo A, Chamberlain C, Navar LG. Augmentation of nitric oxide deficient hypertension by high salt diet is associated with reduced TNF-α receptor type 1 expression in the kidneys. Am J Hypertens. 2024;37(9):717-725.

[85]

Isabelle M, Simonet S, Ragonnet C, et al. Chronic reduction of nitric oxide level in adult spontaneously hypertensive rats induces aortic stiffness similar to old spontaneously hypertensive rats. J Vasc Res. 2012;49:309-318.

[86]

Paulis L, Becker ST, Lucht K, et al. Direct angiotensin II type 2 receptor stimulation in Nω-nitro-L-arginine-methyl ester-induced hypertension: the effect on pulse wave velocity and aortic remodeling. Hypertension. 2012;59:485-492.

[87]

Magalhães Borges V, Horimoto ARVR, Wijsman EM, et al. Genomic exploration of essential hypertension in African-Brazilian Quilombo populations: a comprehensive approach with pedigree analysis and family-based association studies. medRxiv [Preprint]. 2024;26.24309531.

[88]

González-Correa C, Moleón J, Miñano S, et al. Differing contributions of the gut microbiota to the blood pressure lowering effects induced by first-line antihypertensive drugs. Br J Pharmacol. 2024;181(18):3420-3444.

[89]

Mills MC, Rahal C. The GWAS Diversity Monitor tracks diversity by disease in real time. Nat Genet. 2020;52(3):242-243.

[90]

Seidel E, Scholl UI. Genetic mechanisms of human hypertension and their implications for blood pressure physiology. Physiol Genomics. 2017;49(11):630-652.

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