TITLE:
The Spontaneously Hypertensive Rat in the Era of Cardiometabolic Hypertension: Strengths, Limitations and Translational Perspectives
AUTHORS:
María Fernanda Iñigo-Pío, Itzell Alejandrina Gallardo-Ortíz, Rafael Villalobos-Molina, Santiago Cristóbal Sigrist-Flores
KEYWORDS:
Spontaneously Hypertensive Rat, Cardiorenal Injury, Cardiometabolic Hypertension, Translational Research, Metabolic Syndrome, Animal Models
JOURNAL NAME:
Journal of Biosciences and Medicines,
Vol.14 No.9,
September
23,
2026
ABSTRACT: The spontaneously hypertensive rat (SHR) remains a cornerstone model for studying essential hypertension and cardiorenal damage. However, its translational relevance must be interpreted within a clinical context in which hypertension frequently coexists with metabolic abnormalities, including obesity, dyslipidemia, insulin resistance, and impaired glucose regulation, features that the lean, largely normoglycemic SHR does not fully reproduce. This review critically re-evaluates the strengths, methodological limitations, and translational utility of the SHR model in the current era of cardiometabolic hypertension. We highlight that cardiorenal injury in the SHR involves mechanisms that extend beyond pressure overload, including tissue renin-angiotensin-aldosterone system (RAAS) dysregulation, mitochondrial remodeling, and sterile inflammation. Furthermore, we propose that, rather than representing a classic low-output cardiorenal syndrome, the SHR may be better viewed as a model of parallel, progressive cardiac and renal injury driven primarily by pressure overload and neurohormonal mechanisms; a contribution of altered venous hemodynamics remains plausible but unproven. Altered venous capacitance and filling pressures suggest a potential contribution of venous hemodynamics to cardiorenal cross-talk, although renal venous hypertension and chronic renal congestion remain unproven in SHR. Despite these mechanistic insights, significant translational barriers persist, notably the “metabolic gap”, the phenotypic and genetic variability of SHR/Wistar-Kyoto (WKY) substrains, and the confounding impact of environmental variables such as the gut microbiome. To bridge these gaps, future research should integrate high-resolution phenotyping, including single-cell and spatial transcriptomics, proteomics, metabolomics, and targeted interrogation of emerging pathways, to define cell-specific pathogenic mechanisms. Ultimately, the SHR should be recognized not as a universal surrogate for human hypertension, but as a precision mechanistic model whose value depends on the biological question under investigation.