Paradoxical sex differences in a hamster model of angiotensin II-dependent hypertension and associated renal injury

TL;DR

Female Syrian hamsters show greater blood pressure increases and kidney damage than males when exposed to angiotensin II, revealing sex-specific differences in hypertension and kidney disease.

Contribution

A novel Syrian hamster model of angiotensin II-induced hypertension is developed, highlighting sex-specific responses in blood pressure and kidney injury.

Findings

Female hamsters exhibited a 50 mmHg increase in blood pressure compared to 27 mmHg in males after angiotensin II infusion.

Females showed more severe kidney damage, including tubular necrosis, glomerular sclerosis, and vascular injury.

Angiotensin II reduced RAS components (ACE, ACE2, AT1R) and elevated inflammatory markers (IL-6, IL-1β) only in females.

Abstract

Biological sex is a critical determinant in cardiovascular and renal disease outcomes. Although angiotensin II (Ang II) infusion is widely used to model hypertension in mice and rats, little is known about its effects in the Syrian hamster, a small rodent increasingly used for translational research. This study aimed to develop a model of chronic Ang II-induced hypertension in Syrian hamsters and investigate sex-specific differences in blood pressure, renal pathology, and components of the renin-angiotensin system (RAS).

Male and female Syrian hamsters (8–9 weeks old) were infused subcutaneously with Ang II (200 ng/kg/min) or saline via osmotic minipumps for four weeks. Mean arterial pressure (MAP) and kidney wet weight were determined on the euthanasia day. The kidneys were analyzed for renal pathology; renal RAS enzymes (ACE and ACE2) were measured by colorimetric assay and qPCR; cytokines (IL-6 and IL-1β) were measured by qPCR; and the angiotensin receptor type 1 (AT1R) was measured by radioligand binding and qPCR.

Ang II infusion increased MAP in both sexes but elicited a significantly greater response in females (+ 50 mmHg) than males (+ 27 mmHg, p < 0.005). Female hamsters exhibited pronounced kidney injury, including acute tubular necrosis, glomerular sclerosis, and vascular fibrinoid necrosis, along with a 2-fold increase in kidney weight normalized to body weight. Ang II significantly downregulated renal ACE, ACE2, and AT1R expression and activity in females but not in males. Renal IL-6 and IL-1β mRNA levels were elevated 20-fold and 3.9-fold, respectively, in females, compared to modest increases in males.

Female Syrian hamsters exhibit heightened vulnerability to Ang II-induced hypertension and renal damage compared to males, marked by exaggerated blood pressure elevation, enhanced renal inflammation, and suppression of classical RAS components. This novel hamster model provides a unique platform for studying sex-specific mechanisms of hypertension and renal pathology, with translational relevance for subpopulations of women who are at increased risk of Ang II-dependent hypertension-associated renal disease.

High blood pressure (also known as hypertension) is a major risk factor for heart and kidney disease. Men and women often experience these conditions differently, but scientists still don’t fully understand why. In this study, researchers focused on how male and female Syrian hamsters respond to a substance called angiotensin II, which is known to raise blood pressure and is commonly used in research to mimic high blood pressure in animals.

Over four weeks, male and female hamsters were given either angiotensin II or a harmless salt solution. The researchers measured blood pressure and looked at changes in kidney health and in a system of hormones that helps control blood pressure, called the renin-angiotensin system. They found that angiotensin II caused a much bigger rise in blood pressure in female hamsters than in males. The female hamsters also showed more severe kidney damage, including scarring and inflammation. Important hormones and enzymes that usually help regulate blood pressure were found to be lower in females after treatment, while markers of inflammation were much higher.

These results suggest that female hamsters are more sensitive to angiotensin II and may be more at risk of developing severe kidney problems from high blood pressure. This new hamster model offers a valuable way to study how men and women differ in their response to high blood pressure and could help researchers find better, more personalized treatments—especially for women who may be more vulnerable to certain types of hypertension-related kidney disease.

Developed a novel model of angiotensin II-induced hypertension in Syrian hamsters.Female hamsters showed significantly higher increases in blood pressure than males in response to angiotensin II.Females exhibited more severe kidney damage, including tubular necrosis, glomerular sclerosis, and vascular injury.Only in females, angiotensin II reduced key components of the renal renin-angiotensin system (ACE, ACE2, AT1R).Inflammatory markers (IL-6, IL-1β) were dramatically elevated in female kidneys compared to males.

Developed a novel model of angiotensin II-induced hypertension in Syrian hamsters.

Female hamsters showed significantly higher increases in blood pressure than males in response to angiotensin II.

Females exhibited more severe kidney damage, including tubular necrosis, glomerular sclerosis, and vascular injury.

Only in females, angiotensin II reduced key components of the renal renin-angiotensin system (ACE, ACE2, AT1R).

Inflammatory markers (IL-6, IL-1β) were dramatically elevated in female kidneys compared to males.

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