Effects of chymostatin, a chymase inhibitor, on blood pressure, plasma and tissue angiotensin II, renal haemodynamics and renal excretion in two models of hypertension in the rat

Roszkowska-Chojecka, Malwina Monika; Walkowska, Agnieszka; Gawryś, Olga; Baranowska, Iwona; Kalisz, Małgorzata; Litwiniuk, Anna; Martyńska, Lidia; Kompanowska-Jezierska, Elżbieta

doi:10.1113/ep085325

Cited by 20 publications

(16 citation statements)

References 50 publications

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“…Our observations indicate that these cells normally display elements of the RAS including the essential precursor protein AGT, and renin which is requisite for the formation of the ANGII precursor, ANGI. Many peptidases are capable of converting ANGI to ANGII, including chymase 49 which we show was abundant in resident mast cells; others that are likely to participate in ANGII generation are angiotensin converting enzyme I and cathepsin G 40 , both of which are widely distributed in inflamed tissue 11, 25 . Hence, under control and nontender conditions, elements of a vestibular RAS are present but in rather modest numbers (Fig.…”

Section: Discussionmentioning

confidence: 69%

A Local Inflammatory Renin-Angiotensin System Drives Sensory Axon Sprouting in Provoked Vestibulodynia

Liao

Chakrabarty

et al. 2017

The Journal of Pain

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Vestibulodynia is a form of provoked vulvodynia characterized by profound tenderness, hyperinnervation, and frequently inflammation within well-defined areas of the human vestibule. Prior experiments in animal models show that inflammatory hypersensitivity and hyperinnervation occur in concert with establishment of a local renin-angiotensin system (RAS). Moreover, mechanical hypersensitivity and sensory axon sprouting are prevented by blocking effects of angiotensin II on AT2 receptors. This case-control study assessed whether a RAS contributes to hyperinnervation observed in human vestibulodynia. Vestibular biopsies from asymptomatic controls or patients’ nontender areas showed moderate innervation and small numbers of inflammatory cells. In women with vestibulodynia, tender areas contained increased numbers of mechanoreceptive nociceptor axons, T-cells, macrophages and B-cells, while mast cells were unchanged. RAS proteins were increased due to greater numbers of T-cells and B-cells expressing angiotensinogen, and increased renin-expressing T-cells and macrophages. Chymase, which converts angiotensin I to angiotensin II, was present in constant numbers of mast cells. To determine if tender vestibular tissue generates angiotensin II that promotes axon sprouting, we conditioned culture medium with vestibular tissue. Rat sensory neurons cultured in control-conditioned medium showed normal axon outgrowth, while those in tender tissue-conditioned medium showed enhanced sprouting that was prevented by adding an AT2 antagonist or angiotensin II neutralizing antibody. Hypersensitivity in provoked vestibulodynia is therefore characterized by abnormal mechano-nociceptor axon proliferation, which is attributable to inflammatory cell-derived angiotensin II (or a closely related peptide) acting on neuronal AT2 receptors. Accordingly, reducing inflammation or blocking AT2 represent rational strategies to mitigate this common pain syndrome. Perspective: This study provides evidence that local inflammation leads to angiotensin II formation which acts on the angiotensin II receptor type 2 to induce nociceptor axon sprouting in vulvodynia. Preventing inflammation and blocking AT2 therefore present potential pharmacological strategies for reducing vestibular pain.

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Section: Discussionmentioning

confidence: 69%

A Local Inflammatory Renin-Angiotensin System Drives Sensory Axon Sprouting in Provoked Vestibulodynia

Liao

Chakrabarty

et al. 2017

The Journal of Pain

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“…There is a growing body of evidence of renin‐independent and ACE‐independent AngII production via chymase . For example, in the experimental hypertension models, Goldblatt 2‐kidney, 1‐clip model or the unilateral nephrectomy plus HS diet model, in vivo chymase inhibition (with chymostatin) resulted in a significant 75% and 50%, respectively, reduction in renal AngII content . Further study is warranted to determine whether CD NOS1β regulates renal AngII concentration through angiotensinogen uptake and/or chymase activity.…”

Section: Discussionmentioning

confidence: 99%

Collecting Duct Nitric Oxide Synthase 1ß Activation Maintains Sodium Homeostasis During High Sodium Intake Through Suppression of Aldosterone and Renal Angiotensin II Pathways

Hyndman

Mironova

Giani

et al. 2017

JAHA

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BackgroundDuring high sodium intake, the renin‐angiotensin‐aldosterone system is downregulated and nitric oxide signaling is upregulated in order to remain in sodium balance. Recently, we showed that collecting duct nitric oxide synthase 1β is critical for fluid‐electrolyte balance and subsequently blood pressure regulation during high sodium feeding. The current study tested the hypothesis that high sodium activation of the collecting duct nitric oxide synthase 1β pathway is critical for maintaining sodium homeostasis and for the downregulation of the renin‐angiotensin‐aldosterone system–epithelial sodium channel axis.Methods and ResultsMale control and collecting duct nitric oxide synthase 1β knockout (CDNOS1KO) mice were placed on low, normal, and high sodium diets for 1 week. In response to the high sodium diet, plasma sodium was significantly increased in control mice and to a significantly greater level in CDNOS1KO mice. CDNOS1KO mice did not suppress plasma aldosterone in response to the high sodium diet, which may be partially explained by increased adrenal AT1R expression. Plasma renin concentration was appropriately suppressed in both genotypes. Furthermore, CDNOS1KO mice had significantly higher intrarenal angiotensin II with high sodium diet, although intrarenal angiotensinogen levels and angiotensin‐converting enzyme activity were similar between knockout mice and controls. In agreement with inappropriate renin‐angiotensin‐aldosterone system activation in the CDNOS1KO mice on a high sodium diet, epithelial sodium channel activity and sodium transporter abundance were significantly higher compared with controls.ConclusionsThese data demonstrate that high sodium activation of collecting duct nitric oxide synthase 1β signaling induces suppression of systemic and intrarenal renin‐angiotensin‐aldosterone system, thereby modulating epithelial sodium channel and other sodium transporter abundance and activity to maintain sodium homeostasis.

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“…Specific synthetic chymase inhibitors attenuate Ang II production and alleviate renal fibrosis through inhibition of activation of TGF-β in animal models [ 26 ]. Chymostatin is a strong inhibitor of chymases and it can effectively inhibit Ang II production in the kidney [ 27 , 28 ] and ameliorate salt-dependent hypertension [ 29 ].…”

Section: Introductionmentioning

confidence: 99%

Combination of Chymostatin and Aliskiren attenuates ER stress induced by lipid overload in kidney tubular cells

Qiu

Jin

et al. 2018

Lipids Health Dis

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BackgroundLipotoxicity plays an important role in the pathogenesis of kidney injury. Our previous study demonstrated that activation of local renin-angiotensin system (RAS) was involved in saturated free fatty acids palmitic acid (PA)-induced tubular cell injuries. The current study aims to investigate whether suppression of RAS by combination of direct renin inhibitor aliskiren and noncanonical RAS pathway chymase inhibitor chymostatin attenuates PA or cholesterol induced-endoplasmic reticulum stress (ER stress) and apopotosis in cultured human proximal tubular HK2 cells.MethodsHK2 cells were treated with saturated fatty acid PA (0.6 mM) for 24 h or cholesterol (10 μg/ml) for 6d with or without chymostatin and/or aliskiren. Expressions of the ER stress associated proteins and apoptosis markers were detected by western blotting. The mRNA levels of RAS components were measured by real-time qPCR.ResultsCombination treatment of chymostatin and aliskiren markedly suppressed PA or cholesterol-induced ER stress, as reflected by increased BiP, IRE1α, phosphorylated-eIF2α and ATF4 as well as proapoptotic transcription factor CHOP. The ratio of Bax/Bcl-2 and cleaved caspase-3, two markers of apoptosis were upregulated by PA or cholesterol treatment. PA treatment was also associated with increased levels of angiotensinogen and angiotensin type 1 receptor (AT1R) mRNA expression. Combination treatment of chymostatin and aliskiren markedly suppressed PA or cholesterol-induced ER stress and apoptosis. The protective effect of two inhibitors was also observed in primary cultured cortical tubular cells treated with PA. In contrast, chymostatin and/or aliskiren failed to prevent ER stress induced by tunicamycin.ConclusionsThese results suggested that combination treatment of chymostatin and aliskiren attenuates lipid-induced renal tubular cell injury, likely through suppressing activation of intracellular RAS.Electronic supplementary materialThe online version of this article (10.1186/s12944-018-0818-1) contains supplementary material, which is available to authorized users.

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Effects of chymostatin, a chymase inhibitor, on blood pressure, plasma and tissue angiotensin II, renal haemodynamics and renal excretion in two models of hypertension in the rat

Cited by 20 publications

References 50 publications

A Local Inflammatory Renin-Angiotensin System Drives Sensory Axon Sprouting in Provoked Vestibulodynia

A Local Inflammatory Renin-Angiotensin System Drives Sensory Axon Sprouting in Provoked Vestibulodynia

Collecting Duct Nitric Oxide Synthase 1ß Activation Maintains Sodium Homeostasis During High Sodium Intake Through Suppression of Aldosterone and Renal Angiotensin II Pathways

Combination of Chymostatin and Aliskiren attenuates ER stress induced by lipid overload in kidney tubular cells

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