C3 in spontaneously hypertensive rats
The spontaneously hypertensive rat (SHR) is a widely used genetic model
of hypertension. SHRs show exaggerated growth of cardiovascular organs
in comparison with normotensive Wistar-Kyoto (WKY) rats (Sen et al.,
1974). Enhanced DNA synthesis and organ hypertrophy were found to occur
before the elevation of blood pressure in SHRs (Walter & Hamet, 1986).
In addition, SHR-derived vascular smooth muscle cells (VSMC) as well as
mesangial cells in culture show exaggerated growth in comparison with
cells from WKY rats (Chen et al., 2020a). C3 expression is upregulated
in VSMC from SHR compared to normotensive WKY rats. Exogenous C3a
increases cell growth and suppression of C3a generation or C3aR activity
in SHR-derived VSMCs and MCs inhibit cell growth (Ikeda et al., 2014;
Lin et al., 2004). Negishi and colleagues showed that knockout of theC3 gene by zinc-finger nuclease gene-editing in SHRs had a small
but significant effect on systolic blood pressure, proliferation of
mesangial cells and renal injury (Negishi et al., 2018). In contrast,
mice deficient in C3 had similar basal blood pressure compared to wild
type animals and showed no differences in hypertension or hypertrophy
responses to in vivo infusion with angiotensin II (Coles et al.,
2007). However, in this latter study a low dose of angiotensin (1.1
ng/g/min) was given to mice of the C57/BL6 black strain for only 7 days.
7 days of angiotensin infusion induce a mild increase in blood pressure
and vascular hypertrophy but do not induce hypertensive injury.
Therefore, a role for C3 in hypertensive injury cannot be ruled out
based on this study.