Altering Early Life Gut Microbiota Has Long-Term Effect on Immune System and Hypertension in Spontaneously Hypertensive Rats.

Hypertension is regulated by immunological components. Spontaneously hypertensive rats (SHR) display a large population of proinflammatory CD161 + immune cells. We investigated the effect of early post-natal gut microbiota on the development of the immune system and resulting hypertension in the SHR.

TMEM16B determines cholecystokinin sensitivity of intestinal vagal afferents of nodose neurons.

The satiety effects and metabolic actions of cholecystokinin (CCK) have been recognized as potential therapeutic targets in obesity for decades. We identified a potentially novel Ca2+-activated chloride (Cl-) current (CaCC) that is induced by CCK in intestinal vagal afferents of nodose neurons. The CaCC subunit Anoctamin 2 (Ano2/TMEM16B) is the dominant contributor to this current.

Angiotensin II-induced hypertension and cardiac hypertrophy are differentially mediated by TLR3- and TLR4-dependent pathways.

Toll-like receptors (TLR) are key components of the innate immune system that elicit inflammatory responses through the adaptor proteins myeloid differentiation protein 88 (MyD88) and Toll-interleukin receptor domain-containing adaptor protein-inducing interferon-β (TRIF). Previously, we demonstrated that TRIF mediates the signaling of angiotensin II (ANG II)- induced hypertension and cardiac hypertrophy. Since TRIF is activated selectively by TLR3 and TLR4, our goals in this study were to determine the roles of TLR3 and TLR4 in mediating ANG II-induced hypertension and cardiac hypertrophy, and associated changes in proinflammatory gene expression in heart and kidney.

Abnormal CD161 immune cells and retinoic acid receptor-related orphan receptor γt-mediate enhanced IL-17F expression in the setting of genetic hypertension.

Background: Hypertension is considered an immunologic disorder. However, the role of the IL-17 family in genetic hypertension in the spontaneously hypertensive rat (SHR) has not been investigated.

Objective: We tested the hypothesis that enhanced T17 programming and IL-17 expression in abundant CD161 immune cells in SHRs represent an abnormal proinflammatory adaptive immune response.

Dual Activation of TRIF and MyD88 Adaptor Proteins by Angiotensin II Evokes Opposing Effects on Pressure, Cardiac Hypertrophy, and Inflammatory Gene Expression.

Hypertension is recognized as an immune disorder whereby immune cells play a defining role in the genesis and progression of the disease. The innate immune system and its component toll-like receptors are key determinants of the immunologic outcome through their proinflammatory response. Toll-like receptor-activated signaling pathways use several adaptor proteins of which adaptor proteins myeloid differentiation protein 88 (MyD88) and toll-interleukin receptor domain-containing adaptor protein-inducing interferon-β (TRIF) define 2 major inflammatory pathways.

Angiotensin-dependent autonomic dysregulation precedes dilated cardiomyopathy in a mouse model of muscular dystrophy.

What is the central question of this study? Is autonomic dysregulation in a mouse model of muscular dystrophy dependent on left ventricular systolic dysfunction and/or activation of the renin-angiotensin system (RAS) and does it predict development of dilated cardiomyopathy (DCM)? What is the main finding and its importance? The results demonstrate that autonomic dysregulation precedes and predicts left ventricular dysfunction and DCM in sarcoglycan-δ-deficient (Sgcd-/-) mice. The autonomic dysregulation is prevented by treatment of young Sgcd-/- mice with the angiotensin II type 1 receptor blocker losartan. Measurements of RAS activation and autonomic dysregulation may predict risk of DCM, and therapies targeting the RAS and autonomic dysregulation at a young age may slow disease progression in patients.

Chronic oral administration of Ang-(1-7) improves skeletal muscle, autonomic and locomotor phenotypes in muscular dystrophy.

Muscular dystrophies are a group of heterogeneous genetic disorders that cause progressive muscle weakness and wasting, dilated cardiomyopathy and early mortality. There are different types of muscular dystrophies with varying aetiologies but they all have a common hallmark of myofibre degeneration, atrophy and decreased mobility. Mutation in Sgcd (sarcoglycan-δ), a subunit of dystrophin glycoprotein complex, causes LGMD2F (limb girdle muscular dystrophy 2F).

Impaired interaction between efferent and afferent renal nerve activity in SHR involves increased activation of alpha2-adrenoceptors.

Activation of efferent renal sympathetic nerve activity (ERSNA) increases afferent renal nerve activity (ARNA), leading to decreases in ERSNA by activation of the renorenal reflexes in the overall goal of maintaining low ERSNA. The renorenal reflex responses to various stimuli are impaired in spontaneously hypertensive rats (SHR). Because renal tissue density of α(2)-adrenoceptors (ARs) is increased in SHR, we examined whether the ERSNA-induced increases in ARNA are impaired in SHR and, if so, the role of α(2)-ARs.

Dietary sodium modulates the interaction between efferent and afferent renal nerve activity by altering activation of α2-adrenoceptors on renal sensory nerves.

Activation of efferent renal sympathetic nerve activity (ERSNA) increases afferent renal nerve activity (ARNA), which then reflexively decreases ERSNA via activation of the renorenal reflexes to maintain low ERSNA. The ERSNA-ARNA interaction is mediated by norepinephrine (NE) that increases and decreases ARNA by activation of renal α(1)-and α(2)-adrenoceptors (AR), respectively. The ERSNA-induced increases in ARNA are suppressed during a low-sodium (2,470 ± 770% s) and enhanced during a high-sodium diet (5,670 ± 1,260% s).

Activation of endothelin A receptors contributes to impaired responsiveness of renal mechanosensory nerves in congestive heart failure.

Increasing renal pelvic pressure results in PGE2-mediated release of substance P, leading to increases in afferent renal nerve activity (ARNA) and natriuresis, that is, a renorenal reflex response. The renorenal reflexes are impaired in congestive heart failure (CHF). Impairment of the renorenal reflexes may contribute to the increased renal sympathetic nerve activity and sodium retention in CHF.

Dietary sodium modulates the interaction between efferent renal sympathetic nerve activity and afferent renal nerve activity: role of endothelin.

Increasing efferent renal sympathetic nerve activity (ERSNA) increases afferent renal nerve activity (ARNA), which in turn decreases ERSNA via activation of the renorenal reflexes in the overall goal of maintaining low ERSNA. We now examined whether the ERSNA-induced increases in ARNA are modulated by dietary sodium and the role of endothelin (ET). The ARNA response to reflex increases in ERSNA was enhanced in high (HNa)- vs.

Impaired responsiveness of renal sensory nerves in streptozotocin-treated rats and obese Zucker diabetic fatty rats: role of angiotensin.

Increasing afferent renal nerve activity decreases efferent renal nerve activity and increases urinary sodium excretion. Activation of renal pelvic mechanosensory nerves is impaired in streptozotocin (STZ)-treated rats (model of type 1 diabetes). Decreased activation of renal sensory nerves would lead to increased efferent renal nerve activity, sodium retention, and hypertension.

Renal sympathetic nerve activity modulates afferent renal nerve activity by PGE2-dependent activation of alpha1- and alpha2-adrenoceptors on renal sensory nerve fibers.

Increasing efferent renal sympathetic nerve activity (ERSNA) increases afferent renal nerve activity (ARNA). To test whether the ERSNA-induced increases in ARNA involved norepinephrine activating alpha-adrenoceptors on the renal sensory nerves, we examined the effects of renal pelvic administration of the alpha(1)- and alpha(2)-adrenoceptor antagonists prazosin and rauwolscine on the ARNA responses to reflex increases in ERSNA (placing the rat's tail in 49 degrees C water) and renal pelvic perfusion with norepinephrine in anesthetized rats. Hot tail increased ERSNA and ARNA, 6,930 +/- 900 and 4,870 +/- 670%.

Activation of endothelin-a receptors contributes to angiotensin-induced suppression of renal sensory nerve activation.

Activation of renal mechanosensory nerves is enhanced by a high-sodium diet and suppressed by a low-sodium diet. Angiotensin (Ang) II and endothelin (ET)-1 each contributes to the impaired responsiveness of renal mechanosensory nerves in a low-sodium diet. We examined whether stimulation of ETA receptors (Rs) contributes to Ang II-induced suppression of the responsiveness of renal mechanosensory nerves.

Differential effects of endothelin on activation of renal mechanosensory nerves: stimulatory in high-sodium diet and inhibitory in low-sodium diet.

Activation of renal mechanosensory nerves is enhanced by high and suppressed by low sodium dietary intake. Afferent renal denervation results in salt-sensitive hypertension, suggesting that activation of the afferent renal nerves contributes to water and sodium balance. Another model of salt-sensitive hypertension is the endothelin B receptor (ETBR)-deficient rat.

Activation of EP4 receptors contributes to prostaglandin E2-mediated stimulation of renal sensory nerves.

Induction of cyclooxygenase-2 (COX-2) in the renal pelvic wall increases prostaglandin E(2) (PGE(2)) leading to stimulation of cAMP production, which results in substance P (SP) release and activation of renal mechanosensory nerves. The subtype of PGE receptors involved, EP2 and/or EP4, was studied by immunohistochemistry and renal pelvic administration of agonists and antagonists of EP2 and EP4 receptors. EP4 receptor-like immunoreactivity (LI) was colocalized with calcitonin gene-related peptide (CGRP)-LI in dorsal root ganglia (DRGs) at Th(9)-L(1) and in nerve terminals in the renal pelvic wall.

Impaired substance P release from renal sensory nerves in SHR involves a pertussis toxin-sensitive mechanism.

Stretching the renal pelvic wall activates renal mechanosensory nerves by a PGE2-mediated release of substance P via activation of the cAMP-PKA pathway. Renal pelvic ANG II modulates the responsiveness of renal sensory nerves by suppressing the PGE2-mediated activation of adenylyl cyclase via a pertussis toxin (PTX)-sensitive mechanism. In SHR, activation of renal mechanosensory nerves is impaired.

Dietary sodium loading increases arterial pressure in afferent renal-denervated rats.

In rats fed high sodium diet, increasing renal pelvic pressure > or =3 mm Hg activates renal mechanosensory nerves, resulting in a renorenal reflex-induced increase in urinary sodium excretion. The low activation threshold of the renal mechanosensory nerves suggests a role for natriuretic renorenal reflexes in the regulation of arterial pressure and sodium balance. If so, interruption of the afferent renal innervation by dorsal rhizotomy (DRX) at T9-L1 would impair urinary sodium excretion and/or increase arterial pressure during high dietary sodium intake.

Angiotensin blocks substance P release from renal sensory nerves by inhibiting PGE2-mediated activation of cAMP.

Activation of renal sensory nerves involves PGE2-mediated release of substance P (SP) via activation of the cAMP-PKA pathway. The PGE2-mediated SP release is suppressed by a low- and enhanced by a high-sodium (Na+) diet, suggesting an inhibitory effect of ANG. We now examined whether ANG II is present in the pelvic wall and inhibits PGE2-mediated SP release by blocking PGE2-mediated increases in cAMP.

Impaired responsiveness of renal mechanosensory nerves in heart failure: role of endogenous angiotensin.

Increasing renal pelvic pressure results in PGE(2)-mediated release of substance P. Substance P increases afferent renal nerve activity (ARNA), which leads to a reflex increase in urinary sodium excretion (U(Na)V). Endogenous ANG II modulates the responsiveness of renal mechanosensory nerves.

PGE(2) increases release of substance P from renal sensory nerves by activating the cAMP-PKA transduction cascade.

Increasing renal pelvic pressure increases afferent renal nerve activity (ARNA) by a PGE(2)-mediated release of substance P (SP) from renal pelvic nerves. The role of cAMP activation in the PGE(2)-mediated release of SP was studied by examining the effects of the adenylyl cyclase (AC) activator forskolin and AC inhibitor dideoxyadenosine (DDA). Forskolin enhanced the bradykinin-mediated release of SP from an isolated rat renal pelvic wall preparation, from 7.

Endogenous angiotensin modulates PGE(2)-mediated release of substance P from renal mechanosensory nerve fibers.

Increasing renal pelvic pressure increases afferent renal nerve activity (ARNA) by a prostaglandin E2 (PGE2)-mediated release of substance P (SP) from renal pelvic sensory nerves. We examined whether the ARNA responses were modulated by high- and low-sodium diets. Increasing renal pelvic pressure resulted in greater ARNA responses in rats fed a high-sodium than in those fed a low-sodium diet.