No evidence for brain renin–angiotensin system activation during DOCA-salt hypertension

Uijl, Estrellita; Ren, Liwei; Colafella, Katrina M Mirabito; Veghel, Richard van; Garrelds, Ingrid M.; Domenig, Oliver; Poglitsch, Marko; Zlatev, Ivan; Kim, Jae Bum; Huang, Stephen A.; Melton, Lauren; Hoorn, Ewout J.; Foster, Don; Danser, A.H. Jan

doi:10.1042/cs20201239

Cited by 22 publications

(49 citation statements)

References 44 publications

(60 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In this sense, the source of brain Ang II could be represented by circulating Ang II that binds to brain Ang receptors in conditions where the BBB integrity is compromised, such as deoxycorticosterone acetate (DOCA)-salt hypertension. It has been shown that DOCA-salt suppressed plasma and brain Ang II in parallel, while spironolactone simultaneously increased Ang II and lowered blood pressure, indicating that DOCA-salt hypertension is not mediated by brain RAS activation [49]. Contrary to this hypothesis, we have shown that Ang II levels were increased in brainstem neurons from SHRs compared with those from WKY animals.…”

Section: The Ras System In the Braincontrasting

confidence: 98%

Angiotensin-(1-7) and Mas receptor in the brain

Mikusic

Pineda

Gironacci

2021

Exploration of Medicine

View full text Add to dashboard Cite

The renin-angiotensin system (RAS) is a key regulator of blood pressure and electrolyte homeostasis. Besides its importance as regulator of the cardiovascular function, the RAS has also been associated to the modulation of higher brain functions, including cognition, memory, depression and anxiety. For many years, angiotensin II (Ang II) has been considered the major bioactive component of the RAS. However, the existence of many other biologically active RAS components has currently been recognized, with similar, opposite, or distinct effects to those exerted by Ang II. Today, it is considered that the RAS is primarily constituted by two opposite arms. The pressor arm is composed by Ang II and the Ang II type 1 (AT1) receptor (AT1R), which mediates the vasoconstrictor, proliferative, hypertensive, oxidative and pro-inflammatory effects of the RAS. The depressor arm is mainly composed by Ang-(1-7), its Mas receptor (MasR) which mediates the depressor, vasodilatory, antiproliferative, antioxidant and anti-inflammatory effects of Ang-(1-7) and the AT2 receptor (AT2R), which opposes to the effects mediated by AT1R activation. Central Ang-(1-7) is implicated in the control of the cardiovascular function, thus participating in the regulation of blood pressure. Ang-(1-7) also exerts neuroprotective actions through MasR activation by opposing to the harmful effects of the Ang II/AT1R axis. This review is focused on the expression and regulation of the Ang-(1-7)/MasR axis in the brain, its main neuroprotective effects and the evidence regarding its involvement in the pathophysiology of several diseases at cardiovascular and neurological level.

show abstract

Section: The Ras System In the Braincontrasting

confidence: 98%

Angiotensin-(1-7) and Mas receptor in the brain

Mikusic

Pineda

Gironacci

2021

Exploration of Medicine

View full text Add to dashboard Cite

show abstract

“…GFR in healthy SD rats is 1.0±0.04 mL/min per 100 g of body weight. 23 At 5 weeks after the 5/6th Nx procedure, GFR had decreased to 0.38±0.10 mL/min per 100 g of body weight. Neither vehicle nor any treatment affected GFR over the next 4 weeks (Figure 4A).…”

Section: Agt Sirna Is Renoprotectivementioning

confidence: 91%

“…In renal tissue, AGT was quantified by Western blotting and normalized versus GAPDH as described before. 23 Plasma renin concentration (PRC) was measured by quantifying Ang I generation in the presence of excess porcine AGT (detection limit, 0.17 ng Ang I/mL per hour). 24 Ang I was measured by radioimmunoassay.…”

Section: Biochemical Measurementsmentioning

confidence: 99%

Renoprotective Effects of Small Interfering RNA Targeting Liver Angiotensinogen in Experimental Chronic Kidney Disease

et al. 2021

Self Cite

View full text Add to dashboard Cite

Small interfering RNA (siRNA) targeting liver angiotensinogen (AGT) lowers blood pressure, but its effectiveness in hypertensive chronic kidney disease is unknown. Considering that the kidney may generate its own AGT, we assessed the effectiveness of liver-targeted AGT siRNA in the 5/6th Nx (5/6th nephrectomy) rat—a hypertensive chronic kidney disease model. Five weeks after 5/6th Nx (baseline), rats were subjected to vehicle, AGT siRNA, AGT siRNA+losartan, losartan, or losartan+captopril. Baseline mean arterial pressure was 160±6 mm Hg. Over the course of 4 weeks, mean arterial pressure increased further by ≈15 mm Hg during vehicle treatment. This rise was prevented by AGT siRNA. Losartan reduced mean arterial pressure by 37±6 mm Hg and increased plasma Ang (angiotensin) II. Both AGT siRNA and captopril suppressed these effects of losartan, suggesting that its blood pressure–lowering effect relied on stimulation of vasodilator Ang II type 2 receptors by high Ang II levels. Proteinuria and cardiac hypertrophy increased with vehicle, and these increases were comparably abrogated by all treatments. No intervention improved glomerular filtration rate, while siRNA and losartan equally diminished glomerulosclerosis. AGT siRNA±losartan reduced plasma AGT by >95%, and this was accompanied by almost complete elimination of Ang II in kidney and heart, without decreasing renal AGT mRNA. Multiple linear regression confirmed both mean arterial pressure and renal Ang II as independent determinants of proteinuria. In conclusion, AGT siRNA exerts renoprotection in the 5/6th Nx model in a blood pressure–independent manner. This relies on the suppression of renal Ang II formation from liver-derived AGT. Consequently, AGT siRNA may prove beneficial in human chronic kidney disease.

show abstract

“…Indeed, in the present study angiotensins could not be detected in brain tissue without angiotensinogen overexpression, and previous studies even suggested that the small amounts of Ang II that could be detected in the brain are derived from blood, i.e. they do not represent local Ang II synthesis in the brain [7,13]. An important next step would therefore be to demonstrate that tonin-driven brain angiotensinogen cleavage truly has in-vivo relevance in either normal physiology or pathology.…”

Section: In Micementioning

confidence: 43%

“…DOCA-salt treatment will lower circulating RAS activity, and thus a simultaneous up-regulation of the brain RAS would be an indication of a fully independent RAS. Yet, disappointingly, a recent study that used small interfering RNA (siRNA) to selectively silence hepatic angiotensinogen showed that eliminating circulating angiotensinogen also made brain Ang II disappear in the DOCA-salt model [13]. In other words, brain Ang II in this model still relied on hepatic angiotensinogen, and most likely represented Ang II taken up from blood.…”

Section: In Micementioning

confidence: 99%

Fifty years of research on the brain renin–angiotensin system: what have we learned?

2021

Self Cite

View full text Add to dashboard Cite

Although the existence of a brain renin–angiotensin system (RAS) had been proposed five decades ago, we still struggle to understand how it functions. The main reason for this is the virtual lack of renin at brain tissue sites. Moreover, although renin’s substrate, angiotensinogen, appears to be synthesized locally in the brain, brain angiotensin (Ang) II disappeared after selective silencing of hepatic angiotensinogen. This implies that brain Ang generation depends on hepatic angiotensinogen after all. Rodrigues et al. (Clin Sci (Lond) (2021) 135:1353–1367) generated a transgenic mouse model overexpressing full-length rat angiotensinogen in astrocytes, and observed massively elevated brain Ang II levels, increased sympathetic nervous activity and vasopressin, and up-regulated erythropoiesis. Yet, blood pressure and kidney function remained unaltered, and surprisingly no other Ang metabolites occurred in the brain. Circulating renin was suppressed. This commentary critically discusses these findings, concluding that apparently in the brain, overexpressed angiotensinogen can be cleaved by an unidentified non-renin enzyme, yielding Ang II directly, which then binds to Ang receptors, allowing no metabolism by angiotensinases like ACE2 and aminopeptidase A. Future studies should now unravel the identity of this non-renin enzyme, and determine whether it also contributes to Ang II generation at brain tissue sites in wildtype animals. Such studies should also re-evaluate the concept that Ang-(1-7) and Ang III, generated by ACE2 and aminopeptidase A, respectively, have important functions in the brain.

show abstract

No evidence for brain renin–angiotensin system activation during DOCA-salt hypertension

Cited by 22 publications

References 44 publications

Angiotensin-(1-7) and Mas receptor in the brain

Angiotensin-(1-7) and Mas receptor in the brain

Renoprotective Effects of Small Interfering RNA Targeting Liver Angiotensinogen in Experimental Chronic Kidney Disease

Fifty years of research on the brain renin–angiotensin system: what have we learned?

Contact Info

Product

Resources

About