Renal nerves contribute to hypertension in Schlager BPH/2J mice

Abstract

Schlager mice (BPH/2J) are hypertensive due to a greater contribution of the sympathetic nervous system (SNS) and renin angiotensin system (RAS). The kidneys of BPH/2J are hyper-innervated suggesting renal nerves may contribute to the hypertension. We therefore determined the effect of bilateral renal denervation (RD) on hypertension in BPH/2J. Mean arterial pressure (MAP) was measured by radiotelemetry before and for 3 weeks after RD in BPH/2J and BPN/3J. The effects of pentolinium and enalaprilat were examined to determine the contribution of the SNS and RAS respectively. After 3 weeks, MAP was-10.9±2.1 mmHg lower in RD BPH/2J compared to baseline and-2.1±2.2 mmHg in sham BPH/2J (P<0.001, n=8-10). RD had no effect in BPN/3J (P>0.1). The depressor response to pentolinium was greater in BPH/2J than BPN/3J but in both cases the response in RD mice was similar to sham. Enalaprilat decreased MAP more in RD BPH/2J compared to sham (-12 vs-3 mmHg, P<0.001) but had no effect in BPN/3J. RD reduced renal noradrenaline in both strains but more so in BPH/2J. RD reduced renin mRNA and protein, but not plasma renin in BPH/2J to levels comparable with BPN/3J mice. We conclude that renal nerves contribute to hypertension in BPH mice since RD induced a sustained fall in MAP which was associated with a reduction of intrarenal renin expression. The lack of inhibition of the depressor effects of pentolinium and enalaprilat by RD suggests that vasoconstrictor effects of the SNS or RAS are not involved. These findings support the continued use of RD in the treatment of hypertension in humans.

Mechanisms Responsible for Genetic Hypertension in Schlager BPH/2 Mice

“…A major characteristic of the BPH/2 strain is a markedly exaggerated day-night difference in BP, HR, and activity compared to the normotensive BPN/3 (Jackson et al, 2014b), C57/Bl6 (Davern et al, 2009), and hypertensive BPH/ApoE mice (Figure 1; Al-Sharea et al, 2019). This day-night difference was small and did not reach statistical significance in the first telemetry study with BPH/2 mice (McGuire et al, 2007) but has been observed in most if not all subsequent studies (Palma-Rigo et al, 2011; Davern et al, 2014; Jackson et al, 2014b,d, 2016; Stevenson et al, 2017; Gueguen et al, 2019; Watson et al, 2019). Reports of HR measured by the tail-cuff technique are variable as to whether BPH/2 mice are tachycardic (Schlager and Sides, 1997) or not (Schlager, 1974) but radio-telemetric measurement of HR under non-stressed conditions consistently shows that BPH/2 mice have higher HR than the normotensive BPN/3 mice (McGuire et al, 2007; Davern et al, 2009).…”

“…Greater tyrosine hydroxylase staining in the kidney of BPH/2 mice also indicated sympathetic hyperinnervation (Jackson et al, 2013) which has been seen in other models of hypertension such as SHR (Cassis et al, 1985). More recently, renal noradrenaline levels were reported to be markedly greater in BPH/2 compared with BPN/3 mice and bilateral renal denervation was shown to reduce the hypertension by one-third in BPH/2 mice without affecting BP in BPN/3 mice (Gueguen et al, 2019). Interestingly, the hypotensive response may also involve the renin-angiotensin system (RAS) since the enhanced renin mRNA levels in BPH/2 mice were normalized following renal denervation (Gueguen et al, 2019).…”

“…More recently, renal noradrenaline levels were reported to be markedly greater in BPH/2 compared with BPN/3 mice and bilateral renal denervation was shown to reduce the hypertension by one-third in BPH/2 mice without affecting BP in BPN/3 mice (Gueguen et al, 2019). Interestingly, the hypotensive response may also involve the renin-angiotensin system (RAS) since the enhanced renin mRNA levels in BPH/2 mice were normalized following renal denervation (Gueguen et al, 2019). Overall, greater sympathetic drive to the kidneys and possibly more generally, contribute largely to the hypertension in BPH/2 mice.…”

“…BPH/2 mice also have greater renal sympathetic innervation density as identified by tyrosine hydroxylase staining of cortical tubules (Jackson et al, 2013) which is where in human, miR-181a is expressed (Marques et al, 2015). Also, renal denervation reduced the higher renal expression of the renin gene and lowered renal renin levels but had no effect on plasma renin concentrations (Gueguen et al, 2019). In a preliminary abstract report, BPH/2 mice treated with a miR-181a mimic had a reduced level of hypertension and normalized levels of renal renin expression (Jackson et al, 2014a).…”

Mechanisms underlying the effects of renal denervation in renovascular hypertension

“…However, renal denervation (RD) has regained attention with the development of minimally invasive catheter-based technology to selectively ablate the renal nerves in humans [5]. Since then, several clinical and experimental studies have explored the therapeutic value of RD in hypertension and associated adverse complications [2,[6][7][8][9]. Notwithstanding, the data available are still controversial and the underlying mechanisms are not clear yet.…”