Chymase inhibition retards albuminuria in type 2 diabetes.

Chymase released from mast cells produces pro-fibrotic, inflammatory, and vasoconstrictor agents. Studies were performed to test the hypothesis that chronic chymase inhibition provides a renal protective effect in type 2 diabetes. Diabetic (db/db) and control mice (db/m) were chronically infused with a chymase-specific inhibitor or vehicle for 8 weeks.

Sympathoinhibitory Effect of Radiofrequency Renal Denervation in Spontaneously Hypertensive Rats With Established Hypertension.

Background: Radiofrequency ablation of the renal arteries (RF-ABL) has been shown to decrease blood pressure (BP) in drug-resistant hypertensive patients who receive antihypertensive drug therapy. However, there remain questions regarding how RF-ABL influences BP independent of drug therapy and whether complete renal denervation is necessary to maximally lower BP. To study these questions, we examined the cardiovascular, sympathetic, and renal effects produced by RF-ABL of the proximal renal arteries in spontaneously hypertensive rats (SHR) with established hypertension.

Increased angiotensinogen expression, urinary angiotensinogen excretion, and tissue injury in nonclipped kidneys of two-kidney, one-clip hypertensive rats.

In angiotensin II (ANG II)-dependent hypertension, there is an angiotensin type 1 receptor-dependent amplification mechanism enhancing intrarenal angiotensinogen (AGT) formation and secretion in the tubular fluid. To evaluate the role of increased arterial pressure, AGT mRNA, protein expression, and urinary AGT (uAGT) excretion and tissue injury were assessed in both kidneys of two-kidney, one-clip Sprague-Dawley hypertensive rats subjected to left renal arterial clipping (0.25-mm gap).

The role of IL-6 in the physiologic versus hypertensive blood pressure actions of angiotensin II.

Angiotensin II (AngII) is a critical physiologic regulator of volume homeostasis and mean arterial pressure (MAP), yet it also is known to induce immune mechanisms that contribute to hypertension. This study determined the role of interleukin-6 (IL-6) in the physiologic effect of AngII to maintain normal MAP during low-salt (LS) intake, and whether hypertension induced by plasma AngII concentrations measured during LS diet required IL-6. IL-6 knockout (KO) and wild-type (WT) mice were placed on LS diet for 7 days, and MAP was measured 19 h/day with telemetry.

PKC-α-dependent augmentation of cAMP and CREB phosphorylation mediates the angiotensin II stimulation of renin in the collecting duct.

In contrast to the negative feedback of angiotensin II (ANG II) on juxtaglomerular renin, ANG II stimulates renin in the principal cells of the collecting duct (CD) in rats and mice via ANG II type 1 (AT1R) receptor, independently of blood pressure. In vitro data indicate that CD renin is augmented by AT1R activation through protein kinase C (PKC), but the exact mechanisms are unknown. We hypothesize that ANG II stimulates CD renin synthesis through AT1R via PKC and the subsequent activation of cAMP/PKA/CREB pathway.

Transcription factor avian erythroblastosis virus E26 oncogen homolog-1 is a novel mediator of renal injury in salt-sensitive hypertension.

Transcription factor E26 transformation-specific sequence-1 (ETS-1) is a transcription factor that regulates the expression of a variety of genes, including growth factors, chemokines, and adhesion molecules. We recently demonstrated that angiotensin II increases the glomerular expression of ETS-1 and that blockade of ETS-1 ameliorates the profibrotic and proinflammatory effects of angiotensin II. The Dahl salt-sensitive rat is a paradigm of salt-sensitive hypertension associated with local activation of the renin-angiotensin system.

Angiotensin II increases the expression of (pro)renin receptor during low-salt conditions.

Background: Evidence indicates that chronic angiotensin II (AngII) infusion increases (pro)renin receptor ((P)RR) expression in renal inner medullary collecting duct (IMCD) cells. Recently, it has been shown that renal (P)RR expression is augmented during a low-salt (LS) diet. However, the role of AngII in mediating the stimulation of (P)RR during LS conditions is unknown.

Renal angiotensin-converting enzyme is essential for the hypertension induced by nitric oxide synthesis inhibition.

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.

Renoprotective effects of direct renin inhibition in glomerulonephritis.

The development of glomerulonephritis causes glomerular injury and renal dysfunction and is thought to increase renin release, thus activating the renin-angiotensin system (RAS). The aims of this study were to demonstrate activation of the intrarenal RAS and determine the effects of direct renin inhibition (DRI) on the progression of glomerulonephritis. Rats were treated with anti-Thy1.

The absence of intrarenal ACE protects against hypertension.

Activation of the intrarenal renin-angiotensin system (RAS) can elicit hypertension independently from the systemic RAS. However, the precise mechanisms by which intrarenal Ang II increases blood pressure have never been identified. To this end, we studied the responses of mice specifically lacking kidney angiotensin-converting enzyme (ACE) to experimental hypertension.

(Pro)renin receptor mediates both angiotensin II-dependent and -independent oxidative stress in neuronal cells.

The binding of renin or prorenin to the (pro)renin receptor (PRR) promotes angiotensin (Ang) II formation and mediates Ang II-independent signaling pathways. In the central nervous system (CNS), Ang II regulates blood pressure via inducing oxidative stress; however, the role of PRR-mediated Ang II-independent signaling pathways in oxidative stress in the CNS remains undefined. To address this question, Neuro-2A cells were infected with control virus or an adeno-associated virus encoding the human PRR.

The Prorenin and (Pro)renin Receptor: New Players in the Brain Renin-Angiotensin System?

It is well known that the brain renin-angiotensin (RAS) system plays an essential role in the development of hypertension, mainly through the modulation of autonomic activities and vasopressin release. However, how the brain synthesizes angiotensin (Ang) II has been a debate for decades, largely due to the low renin activity. This paper first describes the expression of the vasoconstrictive arm of RAS components in the brain as well as their physiological and pathophysiological significance.

Activation of the renin-angiotensin system by a low-salt diet does not augment intratubular angiotensinogen and angiotensin II in rats.

In angiotensin II (ANG II) infusion hypertension, there is an augmentation of intratubular angiotensinogen (AGT) and ANG II leading to increased urinary AGT and ANG II excretion rates associated with tissue injury. However, the changes in urinary AGT and ANG II excretion rates and markers of renal injury during physiologically induced stimulation of the renin-angiotensin system (RAS) by a low-salt diet remain unclear. Male Sprague-Dawley rats received a low-salt diet (0.

Sexual dimorphism in urinary angiotensinogen excretion during chronic angiotensin II-salt hypertension.

Background: The intrarenal renin-angiotensin system contributes to hypertension by regulating sodium and water reabsorption throughout the nephron. Sex differences in the intrarenal components of the renin-angiotensin system have been involved in the greater incidence of high blood pressure and progression to kidney damage in males than females.

Objective: This study investigated whether there is a sex difference in the intrarenal gene expression and urinary excretion of angiotensinogen (AGT) during angiotensin II (Ang II)-dependent hypertension and high-salt (HS) diet.

Increased renin excretion is associated with augmented urinary angiotensin II levels in chronic angiotensin II-infused hypertensive rats.

Renin expression in principal cells of collecting ducts (CD) is upregulated in angiotensin II (ANG II)-dependent hypertensive rats; however, it remains unclear whether increased CD-derived renin undergoes tubular secretion. Accordingly, urinary levels of renin (uRen), angiotensinogen (uAGT), and ANG II (uANG II) were measured in chronic ANG II-infused Sprague-Dawley rats (80 ng/min for 14 days, n = 10) and sham-operated rats (n = 10). Systolic blood pressure increased in the ANG II rats by day 5 and continued to increase throughout the study (day 13; ANG II: 175 ± 10 vs.

ACE2-mediated reduction of oxidative stress in the central nervous system is associated with improvement of autonomic function.

Oxidative stress in the central nervous system mediates the increase in sympathetic tone that precedes the development of hypertension. We hypothesized that by transforming Angiotensin-II (AngII) into Ang-(1-7), ACE2 might reduce AngII-mediated oxidative stress in the brain and prevent autonomic dysfunction. To test this hypothesis, a relationship between ACE2 and oxidative stress was first confirmed in a mouse neuroblastoma cell line (Neuro2A cells) treated with AngII and infected with Ad-hACE2.

Salt-induced renal injury in SHRs is mediated by AT1 receptor activation.

Objective: This study aimed to examine the effects of salt loading, with or without simultaneous angiotensin receptor blocker (ARB) treatment, on the systemic and tissue renin-angiotensin system (RAS) in spontaneously hypertensive rats (SHRs).

Method: Evaluation was performed early (4 weeks) in the course of salt loading in order to examine initial mediating events of cardiovascular and renal damage produced by salt excess. Four groups of rats were studied.

Soluble form of the (pro)renin receptor is augmented in the collecting duct and urine of chronic angiotensin II-dependent hypertensive rats.

Renin synthesis and secretion by principal cells of the collecting duct are enhanced in angiotensin (Ang) II-dependent hypertension. The presence of renin/(pro)renin and its receptor, the (pro)renin receptor ([P]RR), in the collecting duct may provide a pathway for Ang I generation with further conversion to Ang II. To assess whether (P)RR activation occurs during Ang II-dependent hypertension, we examined renal (P)RR levels and soluble (P)RR excretion in the urine of chronic Ang II-infused rats (80 ng/min; for 2 weeks; n=10) and sham-operated rats (n=10).

Angiotensin II stimulates renin in inner medullary collecting duct cells via protein kinase C and independent of epithelial sodium channel and mineralocorticoid receptor activity.

Collecting duct (CD) renin is stimulated by angiotensin (Ang) II, providing a pathway for Ang I generation and further conversion to Ang II. Ang II stimulates the epithelial sodium channel via the Ang II type 1 receptor and increases mineralocorticoid receptor activity attributed to increased aldosterone release. Our objective was to determine whether CD renin augmentation is mediated directly by Ang II type 1 receptor or via the epithelial sodium channel and mineralocorticoid receptor.

Involvement of the brain (pro)renin receptor in cardiovascular homeostasis.

Rationale: Despite overwhelming evidence of the importance of brain renin-angiotensin system (RAS), the very existence of intrinsic brain RAS remains controversial.

Objective: To investigate the hypothesis that the brain (pro)renin receptor (PRR) is physiologically important in the brain RAS regulation and cardiovascular functions.

Methods And Results: PRR is broadly distributed within neurons of cardiovascular-relevant brain regions.

Angiotensin II type 1 receptor-mediated augmentation of urinary excretion of endogenous angiotensin II in Val5-angiotensin II-infused rats.

Rats infused chronically with Val(5)-Angiotensin (Ang) II exhibit increased urinary excretion of endogenous Ile(5)-Ang II by the 12th day of infusion, suggesting the stimulation of endogenous Ang II formation by Val(5)-Ang II infusion. The present study determined the time course of increased urinary Ang II excretion and the effects of Ang II type 1 receptor blockade (candesartan, 2 mg/kg per day) on the urinary excretion rates of Ile(5)-Ang II in Val(5)-Ang II-infused (80 ng/min) rats. Ile(5)-Ang II was separated from Val(5)-Ang II by high-performance liquid chromatography and measured by radioimmunoassay.

Major role for ACE-independent intrarenal ANG II formation in type II diabetes.

Combination therapy of angiotensin-converting enzyme (ACE) inhibition and AT(1) receptor blockade has been shown to provide greater renoprotection than ACE inhibitor alone in human diabetic nephropathy, suggesting that ACE-independent pathways for ANG II formation are of major significance in disease progression. Studies were performed to determine the magnitude of intrarenal ACE-independent formation of ANG II in type II diabetes. Although renal cortical ACE protein activity [2.

Enhanced distal nephron sodium reabsorption in chronic angiotensin II-infused mice.

Chronic angiotensin II (Ang II) infusions enhance urinary excretion of angiotensinogen, suggesting augmentation of distal nephron sodium reabsorption. To assess whether chronic Ang II infusions (15 ng/min for 2 weeks) enhance distal nephron sodium reabsorption, we compared sodium excretion before and after blockade of the 2 main distal nephron sodium transporters by IV amiloride (5 mg/kg of body weight) plus bendroflumethiazide (12 mg/kg of body weight) in male C57/BL6 anesthetized control mice (n=10) and in chronic Ang II-infused mice (n=8). Chronic Ang II infusions increased systolic blood pressure to 141+/-6 mm Hg compared with 106+/-4 mm Hg in control mice.

Augmentation of endogenous intrarenal angiotensin II levels in Val5-ANG II-infused rats.

In angiotensin II (ANG II)-induced hypertension, intrarenal ANG II levels are increased by AT(1) receptor-mediated ANG II internalization and endogenous ANG II generation. The objective of the present study was to determine the relative contribution of de novo formation of endogenous ANG II. Male Sprague-Dawley rats were divided into three groups: sham operated (n = 6), Val(5)-ANG II infused (n = 16), and Ile(5)-ANG II infused (n = 6).

Angiotensin-converting enzyme-derived angiotensin II formation during angiotensin II-induced hypertension.

The extent to which endogenous angiotensin (Ang) II formation is responsible for increasing kidney Ang II content and blood pressure during Ang II-induced hypertension is unknown. To address this, mice were treated with an Ang-converting enzyme (ACE) inhibitor (ACEi) to block endogenous Ang II formation during chronic Ang II infusions. C57BL/6J male mice (8 to 12 weeks) were subjected to Ang II infusions (400 ng/kg per minute) with or without an ACEi (lisinopril, 100 mg/L in the drinking water) for 12 days.