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.