Angiotensin-converting Enzyme Is a Modifier of Hypertensive End Organ Damage

Abstract

Severe forms of hypertension are characterized by high blood pressure combined with end organ damage. Through the development and refinement of a transgenic rat model of malignant hypertension incorporating the mouse renin gene, we previously identified a quantitative trait locus on chromosome 10, which affects malignant hypertension severity and morbidity. We next generated an inducible malignant hypertensive model where the timing, severity, and duration of hypertension was placed under the control of the researcher, allowing development of and recovery from end organ damage to be investigated. We have now generated novel consomic Lewis and Fischer rat strains with inducible hypertension and additional strains that are reciprocally congenic for the refined chromosome 10 quantitative trait locus. We have captured a modifier of end organ damage within the congenic region and, using a range of bioinformatic, biochemical and molecular biological techniques, have identified angiotensin-converting enzyme as the modifier of hypertension-induced tissue microvascular injury. Reciprocal differences between angiotensin-converting enzyme and the anti-inflammatory tetrapeptide, N-acetyl-Ser-Asp-Lys-Pro in the kidney, a tissue susceptible to end organ damage, suggest a mechanism for the amelioration of hypertension-dependent damage.

Renal disease pathophysiology and treatment: contributions from the rat

“…These lines retain the transgene and either susceptibility or resistance to end-organ damage, on an otherwise resistant or susceptible background (Kantachuvesiri et al, 1999). Whole-renal, microarray-based, gene-expression profiling studies of the parental and congenic strains revealed genes in the congenic region that were differentially expressed between the parental and congenic strains (Liu et al, 2009). This strategy identified angiotensin-converting enzyme Ace as a principal modifier of hypertension-induced microvascular renal injury in the Cyp1a1Ren2 rat model (Liu et al, 2009).…”

“…Whole-renal, microarray-based, gene-expression profiling studies of the parental and congenic strains revealed genes in the congenic region that were differentially expressed between the parental and congenic strains (Liu et al, 2009). This strategy identified angiotensin-converting enzyme Ace as a principal modifier of hypertension-induced microvascular renal injury in the Cyp1a1Ren2 rat model (Liu et al, 2009). The C-domain of Ace is thought to mediate blood pressure control through its action on angiotensin I.…”

“…However, it is now recognized that Ace has other effects, such as cleavage of the naturally occurring tetra-peptide acetyl-N-Ser-Asp-Lys-Pro (AcSDKP) by the N-terminal domain of Ace (Bernstein et al, 2011). AcSDKP has been shown to reverse inflammation, cell proliferation and fibrosis in rat models of hypertension (Liu et al, 2009; Zuo et al, 2013). As predicted, AcSDKP was present at significantly lower levels in the kidneys of the injury-susceptible Fischer rat than in the kidneys of the more protected Lewis rat (Liu et al, 2009).…”

Hyperglycemia and Renin-Dependent Hypertension Synergize to Model Diabetic Nephropathy

“…After 28 weeks, animals were anesthetized (Inactin; 120 mg/kg intraperitoneally) and inulin clearance was determined as described. 25 All procedures were preformed under a UK Home Office license. …”

Brain renin-angiotensin system modifies the blood pressure response to intracerebroventricular cadmium in rats

“…Several other studies, although sometimes reporting incongruous results, nevertheless show a relationship between RAS activity and organ damage, in particular to the kidney and heart (Mercure et al, 2009), and the protective effect on these of therapy with ACEIs, ARBs, or a combination of these drugs (Liu et al, 2009;Sudano and Noll, 2009). The rat heart typically expresses both AT 1 and AT 2 receptors, with a greater prevalence for the first of these.…”