Abstract
We examined the effect of total and afferent renal denervation (RDN) on hypertension and the renin-angiotensin system (RAS) in a rodent model of juvenile-onset polycystic kidney disease (PKD). Lewis Polycystic Kidney (LPK) and control rats received total, afferent or sham RDN by periaxonal application of phenol, capsaicin or normal saline, respectively, and were monitored for 4-weeks. Afferent RDN did not affect systolic blood pressure (SBP) determined by radiotelemetry in either strain (n = 19) while total RDN significantly reduced SBP in Lewis rats 4-weeks post-denervation (total vs. sham, 122 ± 1 vs. 130 ± 2 mmHg, P = 0.002, n = 25). Plasma and kidney renin content determined by radioimmunoassay were significantly lower in LPK vs. Lewis (plasma: 278.2 ± 6.7 vs. 376.5 ± 11.9 ng Ang I/ml/h; kidney: 260.1 ± 6.3 vs. 753.2 ± 37.9 ng Ang I/mg/h, P < 0.001, n = 26). These parameters were not affected by RDN. Intrarenal mRNA expression levels of renin, angiotensinogen, angiotensin-converting enzyme (ACE)2, and angiotensin II receptor type 1a were significantly lower, whereas ACE1 expression was significantly higher in the LPK vs. Lewis (all P < 0.05, n = 26). This pattern of intrarenal RAS expression was not changed by RDN. In conclusion, RDN does not affect hypertension or the RAS in the LPK model and indicates RDN might not be a suitable antihypertensive strategy for individuals with juvenile-onset PKD.
Highlights
We examined the effect of total and afferent renal denervation (RDN) on hypertension and the renin-angiotensin system (RAS) in a rodent model of juvenile-onset polycystic kidney disease (PKD)
Upregulation of intrarenal RAS components including renin, angiotensin-converting enzyme (ACE) and angiotensin II (Ang II) has been described in a rodent model of autosomal recessive PKD (ARPKD)[10] and similar findings were seen in mouse models with loss of cilia or polycystin 1, where cyst formation and increased blood pressure were associated with increased kidney angiotensinogen (AGT) levels[11]
The major findings of our study are that neither total nor afferent RDN affects blood pressure, autonomic or renal function in Lewis Polycystic Kidney (LPK) animals and that total RDN, but not selective afferent ablation, produces a modest blood pressure reduction in Lewis control animals
Summary
We examined the effect of total and afferent renal denervation (RDN) on hypertension and the renin-angiotensin system (RAS) in a rodent model of juvenile-onset polycystic kidney disease (PKD). Intrarenal mRNA expression levels of renin, angiotensinogen, angiotensinconverting enzyme (ACE)[2], and angiotensin II receptor type 1a were significantly lower, whereas ACE1 expression was significantly higher in the LPK vs Lewis (all P < 0.05, n = 26) This pattern of intrarenal RAS expression was not changed by RDN. Upregulation of intrarenal RAS components including renin, angiotensin-converting enzyme (ACE) and Ang II has been described in a rodent model of autosomal recessive PKD (ARPKD)[10] (in the absence of any changes in systemic Ang) and similar findings were seen in mouse models with loss of cilia or polycystin 1, where cyst formation and increased blood pressure were associated with increased kidney angiotensinogen (AGT) levels[11]. To date randomized clinical trials examining the impact of RDN in patients with PKD is lacking[17], with only a limited number of case reports available, that do report a blood pressure lowering r esponse[18,19]
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