Rationale: Kidney homeostasis is critically determined by the coordinated activity of the renin-angiotensin system (RAS) including the balanced synthesis of its main effector peptides angiotensin (Ang) II and Ang-(1-7). The condition of enzymatic overproduction of Ang II relative to Ang- (1-7) is termed RAS dysregulation, and leads to cellular signals, which promote hypertension and organ damage, and ultimately progressive kidney failure. Angiotensin-converting enzyme 2 (ACE2) and neprilysin (NEP) induce the 'alternative', and potentially reno-protective axis by enhancing Ang-(1-7) production. However, their individual contribution to baseline RAS balance and whether their activities change in chronic kidney disease (CKD), has not yet been elucidated. Objective: To examine whether NEP-mediated Ang-(1-7) generation exceeds Ang II formation in the healthy kidney compared to diseased kidney. Methods and Results: In this exploratory study, we used mass spectrometry (LC-MS/MS) to measure Ang II and Ang-(1-7) synthesis rates of ACE, chymase and NEP, ACE2, prolyl-endopeptidase (PEP), prolyl-carboxypeptidase (PCP) in kidney biopsy homogenates in 11 healthy living kidney donors and 12 patients with CKD. Spatial expression of RAS enzymes was determined by immunohistochemistry. Healthy kidneys showed higher NEP-mediated Ang-(1-7) synthesis than Ang II formation, thus displaying a strong preference towards the reno-protective alternative RAS axis. In contrast, in CKD kidneys higher levels of Ang II were recorded, which originated from mast cell chymase activity. Conclusions: Ang-(1-7) is the dominant RAS peptide in healthy human kidneys with NEP rather than ACE2 being essential for its generation. Severe RAS dysregulation is present in CKD dictated by high chymase-mediated Ang II formation. Kidney RAS enzyme analysis might lead to novel therapeutic approaches for CKD.

BackgroundIncreased nerve activity causes hypertension and kidney disease. Recent studies suggest that renal denervation reduces BP in patients with hypertension. Renal NE release is regulated by prejunctional α2A-adrenoceptors on sympathetic nerves, and α2A-adrenoceptors act as autoreceptors by binding endogenous NE to inhibit its own release. However, the role of α2A-adrenoceptors in the pathogenesis of hypertensive kidney disease is unknown.MethodsWe investigated effects of α2A-adrenoceptor–regulated renal NE release on the development of angiotensin II–dependent hypertension and kidney disease. In uninephrectomized wild-type and α2A-adrenoceptor–knockout mice, we induced hypertensive kidney disease by infusing AngII for 28 days.ResultsUrinary NE excretion and BP did not differ between normotensive α2A-adrenoceptor–knockout mice and wild-type mice at baseline. However, NE excretion increased during AngII treatment, with the knockout mice displaying NE levels that were significantly higher than those of wild-type mice. Accordingly, the α2A-adrenoceptor–knockout mice exhibited a systolic BP increase, which was about 40 mm Hg higher than that found in wild-type mice, and more extensive kidney damage. In isolated kidneys, AngII-enhanced renal nerve stimulation induced NE release and pressor responses to a greater extent in kidneys from α2A-adrenoceptor–knockout mice. Activation of specific sodium transporters accompanied the exaggerated hypertensive BP response in α2A-adrenoceptor–deficient kidneys. These effects depend on renal nerves, as demonstrated by reduced severity of AngII-mediated hypertension and improved kidney function observed in α2A-adrenoceptor–knockout mice after renal denervation.ConclusionsOur findings reveal a protective role of prejunctional inhibitory α2A-adrenoceptors in pathophysiologic conditions with an activated renin-angiotensin system, such as hypertensive kidney disease, and support the concept of sympatholytic therapy as a treatment.

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