Involvement of complement 3 in the salt-sensitive hypertension by activation of renal renin-angiotensin system in spontaneously hypertensive rats

Abstract

We previously showed that complement 3 (C3) is highly expressed in mesenchymal tissues in spontaneously hypertensive rats (SHR). We targeted C3 gene by zinc-finger nuclease (ZFN) gene-editing technology and investigated blood pressure and phenotype in SHR. Blood pressure was measured by tail-cuff and telemetry methods. Histology and expression of liver X receptor α (LXRα), renin, Krüppel-like factor 5 (KLF5), and E-cadherin were evaluated in kidneys. Mesangial cells (MCs) were removed from glomeruli from three strains, and we evaluated the phenotype in vitro. SHR showed the salt-sensitive hypertension that was abolished in C3 knockout (KO) SHR. Proliferation of MCs from SHR was higher than that from Wistar-Kyoto (WKY) rats and showed a synthetic phenotype. Renal injury scores were higher in SHR than in WKY rats and C3 KO SHR. Expression of E-cadherin was lower, and expression of renin was higher in the nephrotubulus from SHR than WKY rats and C3 KO SHR. Expression of C3 α-chain protein and α-smooth muscle actin protein was significantly higher in renal medulla from SHR than from WKY rats. Expression of angiotensinogen, LXRα, renin, and KLF5 mRNA was increased in kidney from SHR compared with C3 KO SHR. Intrarenal angiotensin II levels were significantly higher in kidney from SHR than WKY rats and C3 KO SHR. Urinary epinephrine and norepinephrine excretions were significantly higher in SHR than in WKY rats and C3 KO SHR. These findings showed that increased C3 induces salt-sensitive hypertension with increases in urinary catecholamine excretion and intrarenal activation of the renin-angiotensin system by the dedifferentiation of mesenchymal tissues in kidney from SHR.

Faculty Opinions recommendation of Impact of hypertensive emergency and complement rare variants on presentation and outcome of atypical hemolytic uremic syndrome.

“…A major involvement of the renin-angiotensin system during HE-aHUS has been demonstrated in the stroke prone spontaneously hypertensive rat model. 21 Interestingly, C3 is involved in the phenotype of this model, 22 and renin has been shown to cleave C3, an effect inhibited by a direct renin inhibitor. 23,24 Renin-angiotensin system activation is also correlated with hemolysis in HE patients.…”

Search for New Candidate Genes Involved in the Comorbidity of Asthma and Hypertension Based on Automatic Analysis of Scientific Literature

“…Hypomethylation of the TLR2 gene increased the risk of essential hypertension in the Chinese population [42]. It was shown that C3 is highly expressed in mesenchymal tissues in spontaneously hypertensive rats (SHR) [43] and increased C3 induces salt-sensitive hypertension in SHR [44]. In [45] was discussed that IL-13 was involved in the induction of pulmonary hypertension.…”

Complement in Renal Disease as a Potential Contributor to Arterial Hypertension

“…Complement activation was also seen in an angiotensin II-induced hypertension model in mice. In spontaneously hypertensive rats, C3 deficiency could abolish salt-sensitive hypertension [18], indicating that C3 is critical involved in hypertensioninducing pathways. However, these effects can also be mediated further downstream in the complement cascade.…”

“…In the rat DOCAsalt hypertension model, glomerular C3 deposition was increased in DOCA-salt rats and decreased by antihypertensive therapy, that is, spironolactone and triple therapy with hydrochlorothiazide, reserpine, and hydralazine [13]. Recent studies using preclinical models of hypertension suggested a role of complement in the pathogenesis of hypertension [14] mediated by different immune cells like macrophages and regulatory Tcells (Tregs) [15][16][17] and activation of the renin-angiotensin system leading to phenotypic changes in vascular smooth muscle cells [18]. The detailed role of renal complement deposition in the development of elevated BP is still unclear.…”