Abstract
Pharmacological inhibition of the renin–angiotensin–aldosterone system (RAAS) is, in combination with diuretics, the first-choice treatment for hypertension, although 10–20% of patients do not respond adequately. Next to the RAAS, the nitric oxide/cGMP/protein kinase G (PKG) system is the second fundamental blood pressure regulator. Whether both systems influence each other is not well-studied. It has been shown that nitric oxide (NO) supports renin recruitment via activation of soluble guanylate cyclase (sGC) and subsequent generation of cGMP. Whether this leads to an ensuing activation of PKGs in this context is not known. PKGIα, as well as PKGII, is expressed in renin-producing cells. Hence, we analyzed whether these enzymes play a role regarding renin synthesis, secretion, or recruitment. We generated renin-cell-specific PKGI-knockout mice and either stimulated or inhibited the renin system in these mice by salt diets. To exclude the possibility that one kinase isoform can compensate the lack of the other, we also studied double-knockout animals with a conditional knockout of PKGI in juxtaglomerular cells (JG cells) and a ubiquitous knockout of PKGII. We analyzed blood pressure, renin mRNA and renal renin protein content as well as plasma renin concentration. Furthermore, we stimulated the cGMP system in these mice using BAY 41-8543, an sGC stimulator, and examined renin regulation either after acute administration or after 7 days (application once daily). We did not reveal any striking differences regarding long-term renin regulation in the studied mouse models. Yet, when we studied the acute effect of BAY 41-8543 on renin secretion in isolated perfused kidneys as well as in living animals, we found that the administration of the substance led to a significant increase in plasma renin concentration in control animals. This effect was completely abolished in double-knockout animals. However, after 7 days of once daily application, we did not detect a persistent increase in renin mRNA or protein in any studied genotype. Therefore, we conclude that in mice, cGMP and PKG are involved in the acute regulation of renin release but have no influence on long-term renin adjustment.
Highlights
The nitric oxide (NO)/cGMP system and the renin–angiotensin–aldosterone system (RAAS) are both crucial players in blood pressure (BP) regulation and can be seen as two scale pans in BP balance
We studied cGMP effects upon soluble guanylate cyclase (sGC) stimulation in these animals and in isolated perfused kidneys (IPN)
Thereby, we have shown that cGMP/protein kinase G (PKG) does not alter chronic renin balance regarding renin release and recruitment but is involved in acute changes of renin secretion
Summary
The NO/cGMP system and the renin–angiotensin–aldosterone system (RAAS) are both crucial players in blood pressure (BP) regulation and can be seen as two scale pans in BP balance. Because upregulation of plasma renin concentration (PRC) leads to hypertension and organ damage in humans, it would be of great importance to understand the underlying signaling mechanisms that trigger renin synthesis, secretion, and recruitment. CAMP is one of the best investigated second messengers in this context This molecule plays a fundamental role in control points of renin activity regarding regulation of renin gene transcription and renin secretion. Regarding modulation of renin synthesis, it is commonly accepted that transcriptional regulation via different regions within the renin gene is the most essential step (Pan and Gross, 2005; Martinez et al, 2018). The cAMP/ CRE/CREB system is an important transcription factor system involved in renin gene regulation (Pan et al, 2001). Whether cGMP/PKG affects renin gene transcription is only partially characterized so far (Wagner et al, 1998)
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