Renal Angiotensin-Converting Enzyme Is Essential for the Hypertension Induced by Nitric Oxide Synthesis Inhibition

Abstract

The kidney is an important source of angiotensin-converting enzyme (ACE) in many species, including humans. However, the specific effects of local ACE on renal function and, by extension, BP control are not completely understood. We previously showed that mice lacking renal ACE, are resistant to the hypertension induced by angiotensin II infusion. Here, we examined the responses of these mice to the low-systemic angiotensin II hypertensive model of nitric oxide synthesis inhibition with L-NAME. In contrast to wild-type mice, mice without renal ACE did not develop hypertension, had lower renal angiotensin II levels, and enhanced natriuresis in response to L-NAME. During L-NAME treatment, the absence of renal ACE was associated with blunted GFR responses; greater reductions in abundance of proximal tubule Na + /H + exchanger 3, Na + /Pi co-transporter 2, phosphorylated Na + /K + /Cl 2 cotransporter, and phosphorylated Na + /Cl 2 cotransporter; and greater reductions in abundance and processing of the g isoform of the epithelial Na + channel. In summary, the presence of ACE in renal tissue facilitates angiotensin II accumulation, GFR reductions, and changes in the expression levels and post-translational modification of sodium transporters that are obligatory for sodium retention and hypertension in response to nitric oxide synthesis inhibition.

Renal Generation of Angiotensin II and the Pathogenesis of Hypertension

“…Similar observations were made during hypertension induced by nitric oxide synthase inhibition with L-NAME (L-NAME induced hypertension) [40]. In this model, the protection against the hypertension by the lack of renal ACE was even more pronounced; while wild-type mice became hypertensive, the blood pressure of ACE 10/10 mice remained essentially unchanged (Fig.…”

Transcutaneous Assessment of Renal Function in Conscious Rodents

“…One of them is the independence from blood and urine sampling which leads to great savings in terms of consumables, time and, of course, animal stress. Table 2, the exogenous renal marker FITC-sinistrin and the measurement of its elimination kinetics through the skin allow the impact of renal pathologies on kidney function to be studied 9,10,[14][15][16][17][18] . The serial collection of blood samples required to assess plasma clearance or biomarkers of renal disease are stressful for the animal, cumbersome and time-consuming for the researchers.…”

Renal Angiotensin-Converting Enzyme Upregulation

“…In fact, according to the authors, the renal Ang II levels of these mice were similar to those of wildtype animals at baseline and remained unchanged during treatment with L-NAME, even though their renal ACE levels were reduced by 90% or more. 13,14 This is a surprising finding that merits further discussion. The most logical explanation of these findings is that these mice, like humans during ACE inhibitor treatment, display increased renin levels.…”

“…12 In this issue of JASN, Giani et al report on the importance of renal ACE in the NOS inhibition model. 13 Their aim was to obtain further evidence for the independency of renal Ang II production (by renal ACE) as a determinant of hypertension. To this end, they used mice that, via targeted homologous recombination, expressed ACE only in myelomonocytic cells (ACE 10/10 mice).…”

“…9 Although the authors emphasize that renal ACE is completely absent in ACE 10/10 mice, there appears to be residual renal ACE staining with immunoblot. 13 In addition, macrophages of ACE 10/10 mice have upregulated ACE and produce more NO, thus potentially compensating for the absence of renal ACE. 15 Importantly, Giani et al demonstrate that NOS inhibition in the low-renal ACE mice does not result in hypertension, cardiac hypertrophy, or proteinuria.…”