Jasn2512editorial 2679..2687
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EDITORIALS www.jasn.org UP FRONT MATTERS Despite their common source of angiotensinogen, circu- Renal Angiotensin-Converting lating and renal Ang II production do not always run in Enzyme Upregulation: A parallel. For instance, in patients with diabetes, plasma reninislow,andyettheir renalplasmaflow response to RAS Prerequisite for Nitric Oxide blockade is greatly enhanced, suggesting an overactive Synthase Inhibition–Induced intrarenal RAS.8 The opposite occurs after treatment with very high doses of a renin inhibitor.9 RAS blockers, by interfering Hypertension? with the negative feedback loop between Ang II and renin release, normally upregulate renin synthesis. Particularly † † Lodi C.W. Roksnoer,* Ewout J. Hoorn, and after high doses this upregulation may be .100-fold.9 Re- A.H. Jan Danser* nin inhibitors selectively accumulate in renal tissue, and, *Division of Pharmacology and Vascular Medicine and †Division of therefore, after stopping treatment,10 renal RAS suppres- Nephrology and Transplantation, Department of Internal Medicine, sion will continue, so that renin release stays high. At the Erasmus MC, Rotterdam, The Netherlands same time the inhibitor starts to disappear from plasma, J Am Soc Nephrol 25: 2679–2681, 2014. and thus insufficient renin inhibitor is around to block all doi: 10.1681/ASN.2014060549 renin molecules that continue to be released. As a conse- quence, plasma renin activity will increase, and extrarenal Ang II and aldosterone levels may even rise to levels above Angiotensin II (Ang II) production at tissue sites is well baseline.9 established. Interference with such local generation, rather The hypertension occurring in animals during inhibition than with Ang II generation in the circulation, is believed to of nitric oxide synthase (NOS) with L-NG-nitroarginine underlie the beneficial cardiovascular and renal effects of methyl ester (L-NAME) is also believed to involve a discrep- renin-angiotensin system (RAS) blockers. Infusion studies ancy between the circulating and renal RAS.11 This concept is with 125I-Ang I and II, allowing the quantification of tissue based on the observation that RAS blockers lower BP in this uptake of circulating angiotensins, have unequivocally con- model, despite the fact that circulating renin is suppressed. firmed that most tissue Ang II is not derived from blood This renin suppression, however, appears to be transient be- but is of local origin.1 For instance, in the kidney, .95% cause long-term L-NAME treatment increases plasma renin of tissue Ang II is generated at renal tissue sites from lo- levels.12 cally synthesized Ang I. This generation depends on renal In this issue of JASN,Gianiet al. report on the importance angiotensin-converting enzyme (ACE), and not chymase, of renal ACE in the NOS inhibition model.13 Their aim was as evidenced by ACE knockout studies and studies with ACE to obtain further evidence for the independency of renal inhibitors.1,2 Initially, it was thought that the angiotensinogen Ang II production (by renal ACE) as a determinant of required for this local production was also kidney derived hypertension. Tothis end, they used mice that, via targeted because angiotensinogen production had been observed in homologous recombination, expressed ACE only in the proximal straight tubule.3,4 However, elegant studies by myelomonocytic cells (ACE 10/10 mice). Such mice are Matsusaka et al. selectively knocking out angiotensinogen phenotypically normal (i.e., they have normal BP and display synthesis in the kidney or liver revealed that only hepatic no renal abnormalities). In fact, according to the authors, the deletion affected renal Ang II, under both normal and renal Ang II levels of these mice were similar to those of wild- pathologic conditions.5,6 Apparently, therefore, kidney- type animals at baseline and remained unchanged during treat- derived angiotensinogen does not contribute to renal ment with L-NAME, even though their renal ACE levels were Ang II production and appears unconverted in urine. In reduced by 90% or more.13,14 This is a surprising finding that humans, urinary angiotensinogen closely follows albu- merits further discussion. The most logical explanation of min excretion and is therefore exclusively plasma (i.e., liver) these findings is that these mice, like humans during ACE 7 derived. inhibitor treatment, display increased renin levels. In hu- mans the return of Ang II to baseline levels, despite ongoing Published online ahead of print. Publication date available at www.jasn.org. ACE inhibition, is called Ang II escape. In case of 90% ACE fi Correspondence: inhibition, a 10-fold rise in renin is suf cient to achieve this, A.H. Jan Danser, PhD, Division of Pharmacology and . Vascular Medicine, Department of Internal Medicine, Room EE1418b, Erasmus and as described above even renin increases of 100-fold are MC, Wytemaweg 80, 3015 CN Rotterdam, The Netherlands. Email: a.danser@ feasible.9 erasmusmc.nl Although the authors emphasize that renal ACE is com- Copyright © 2014 by the American Society of Nephrology pletely absent in ACE 10/10 mice, there appears to be residual J Am Soc Nephrol 25: 2679–2687, 2014 ISSN : 1046-6673/2512-2679 2679 EDITORIALS www.jasn.org renal ACE staining with immunoblot.13 In addition, macro- vessels17 (i.e., the usual site of renin cell upregulation during phages of ACE 10/10 mice have upregulated ACE and produce ACE inhibition). In other words, L-NAME might have inter- more NO, thus potentially compensating for the absence of renal fered with the delicate balance in the ACE 10/10 mice that ACE.15 allowed the restoration of the renal Ang II levels. From this Importantly, Giani et al. demonstrate that NOS inhibition point of view it would have been no surprise if the ACE 10/10 in the low-renal ACE mice does not result in hypertension, mice had shown no change in renin or even a renin decrease cardiac hypertrophy, or proteinuria. In addition, L-NAME did after treatment with L-NAME. To partially address this point, not lead to the acute reduction in GFR or sodium retention the authors measured total renin in plasma. Unfortunately, that was observed in wild-type mice. If anything, they dis- this measurement involved the simultaneous detection of played an acute natriuresis and no change in GFR. The authors prorenin, the inactive precursor of renin, and thus no clear meticulously studied all relevant sodium transporters, in- conclusions can be drawn on the actual changes in plasma cluding the sodium hydrogen exchanger, sodium potassium renin. The variation in total renin is much larger in the ACE chloride cotransporter, sodium chloride cotransporter, and 10/10 mice, and although neither BP nor total renin signifi- epithelial sodium channel. Although the natriuresis in the cantly decreased after L-NAME treatment, total renin levels ACE 10/10 mice occurred during the first week of L-NAME did correlate with change in systolic BP in these animals. This treatment, most transporters still showed a greater downregu- is difficult to understand and might imply that BP in these lation after 4 weeks of L-NAME. The authors attribute this to animals is more renin-dependent, again supporting the renin the fact that the wild-type mice, unlike the ACE 10/10 mice, upregulation in this model. displayed a rise in renal Ang II after L-NAME. Such a global In summary, the impressive studies by Giani et al. confirm effect on sodium transporters is uncommon and intriguing, the importance of renal Ang II upregulation for the hyper- but the proposed model of tubular Ang II affecting sodium tensive effects after L-NAME infusion. This obviously de- transporters via apical Ang II type 1 receptors requires ex- pends on ACE, as all Ang II generation does, but to what perimental proof.14 Theauthorsassumetheriseinrenal degree renal ACE—rather than renin upregulation—is the Ang II to be due to the approximate 2-fold rises in both renal permissive factor cannot yet be said. The ACE 10/10 model ACE and angiotensinogen, which did not occur in the ACE most likely is a high-renin model, at least in the kidney, and 10/10 mice. Surprisingly, however, Giani et al. did not study may thus be less responsive to agents that induce hyperten- renal renin expression, which usually displays much larger sion by inducing renal renin expression. An important ques- rises (as discussed above) than the modest rises observed tion is why NOS inhibition would increase renal Ang II at all. here for ACE and angiotensinogen. On this basis, renin is The answer may lie in the complicated consequences of non- actually more likely to determine the changes in (renal) Ang selective NOS inhibition, affecting endothelial, inducible, II levels. Indeed, a study of the ACE insertion/deletion poly- and neuronal NOS simultaneously, thereby reducing not morphism in humans observed that the 60%–70% higher tis- only the effect of NO on renin release and renin cell recruit- sue ACE levels in DD participants versus II participants had ment but also its capacity to suppress the sympathetic ner- no effect whatsoever on renin or Ang II.16 This implies that vous system.11,12 The sympathetic nervous system interacts normal ACE levels are non–rate-limiting. The doubling of at various levels with the RAS, for example by increasing re- angiotensinogen in wild-type mice is in full agreement with nin release, but also directly with kidney sodium transport.18 the doubling of proteinuria after L-NAME and supports the Therefore, to fully understand these issues, we need to know enhanced leakage of circulating angiotensinogen from plasma notonlythechangesinrenalandplasmareninbutalsothe proposed by Matsusaka et al. as the source of increased renal degree of sympathetic nervous system activation in this Ang II generation.5,6 model. Of interest, renal angiotensinogen in the ACE 10/10 mice was lower than in wild-type mice.