Molecular Mechanisms of Kidney Injury and Repair in Arterial Hypertension

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Abstract

The global burden of chronic kidney disease is rising. The etiologies, heterogeneous, and arterial hypertension, are key factors contributing to the development and progression of chronic kidney disease. Arterial hypertension is induced and maintained by a complex network of systemic signaling pathways, such as the hormonal axis of the renin-angiotensin-aldosterone system, hemodynamic alterations affecting blood flow, oxygen supply, and the immune system. This review summarizes the clinical and histopathological features of hypertensive kidney injury and focusses on the interplay of distinct systemic signaling pathways, which drive hypertensive kidney injury in distinct cell types of the kidney. There are several parallels between hypertension-induced molecular signaling cascades in the renal epithelial, endothelial, interstitial, and immune cells. Angiotensin II signaling via the AT1R, hypoxia induced HIFα activation and mechanotransduction are closely interacting and further triggering the adaptions of metabolism, cytoskeletal rearrangement, and profibrotic TGF signaling. The interplay of these, and other cellular pathways, is crucial to balancing the injury and repair of the kidneys and determines the progression of hypertensive kidney disease.

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Most cited references 53

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Inflammation, immunity, and hypertensive end-organ damage.

William G McMaster, Annet Kirabo, Meena S Madhur … (2015)

For >50 years, it has been recognized that immunity contributes to hypertension. Recent data have defined an important role of T cells and various T cell-derived cytokines in several models of experimental hypertension. These studies have shown that stimuli like angiotensin II, deoxycorticosterone acetate-salt, and excessive catecholamines lead to formation of effector like T cells that infiltrate the kidney and perivascular regions of both large arteries and arterioles. There is also accumulation of monocyte/macrophages in these regions. Cytokines released from these cells, including interleukin-17, interferon-γ, tumor necrosis factorα, and interleukin-6 promote both renal and vascular dysfunction and damage, leading to enhanced sodium retention and increased systemic vascular resistance. The renal effects of these cytokines remain to be fully defined, but include enhanced formation of angiotensinogen, increased sodium reabsorption, and increased renal fibrosis. Recent experiments have defined a link between oxidative stress and immune activation in hypertension. These have shown that hypertension is associated with formation of reactive oxygen species in dendritic cells that lead to formation of gamma ketoaldehydes, or isoketals. These rapidly adduct to protein lysines and are presented by dendritic cells as neoantigens that activate T cells and promote hypertension. Thus, cells of both the innate and adaptive immune system contribute to end-organ damage and dysfunction in hypertension. Therapeutic interventions to reduce activation of these cells may prove beneficial in reducing end-organ damage and preventing consequences of hypertension, including myocardial infarction, heart failure, renal failure, and stroke.

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Endovascular ultrasound renal denervation to treat hypertension (RADIANCE-HTN SOLO): a multicentre, international, single-blind, randomised, sham-controlled trial

Laura Mauri, Michel Azizi, Roland E Schmieder … (2018)

Early studies suggest that radiofrequency-based renal denervation reduces blood pressure in patients with moderate hypertension. We investigated whether an alternative technology using endovascular ultrasound renal denervation reduces ambulatory blood pressure in patients with hypertension in the absence of antihypertensive medications.

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T regulatory lymphocytes prevent angiotensin II-induced hypertension and vascular injury.

Tlili Barhoumi, Pascal Laurant, Pierre Paradis … (2011)

Angiotensin (Ang) II induces hypertension by mechanisms mediated in part by adaptive immunity and T effector lymphocytes. T regulatory lymphocytes (Tregs) suppress T effector lymphocytes. We questioned whether Treg adoptive transfer would blunt Ang II-induced hypertension and vascular injury. Ten- to 12-week-old male C57BL/6 mice were injected IV with 3 ×10(5) Treg (CD4(+)CD25(+)) or T effector (CD4(+)CD25(-)) cells, 3 times at 2-week intervals, and then infused or not with Ang II (1 μg/kg per minute, SC) for 14 days. Ang II increased systolic blood pressure by 43 mm Hg (P<0.05), NADPH oxidase activity 1.5-fold in aorta and 1.8-fold in the heart (P<0.05), impaired acetylcholine vasodilatory responses by 70% compared with control (P<0.05), and increased vascular stiffness (P<0.001), mesenteric artery vascular cell adhesion molecule expression (2-fold; P<0.05), and aortic macrophage and T-cell infiltration (P<0.001). All of the above were prevented by Treg but not T effector adoptive transfer. Ang II caused a 43% decrease in Foxp3(+) cells in the renal cortex, whereas Treg adoptive transfer increased Foxp3(+) cells 2-fold compared with control. Thus, Tregs suppress Ang II-mediated vascular injury in part through anti-inflammatory actions. Immune mechanisms modulate Ang II-induced blood pressure elevation, vascular oxidative stress, inflammation, and endothelial dysfunction.

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Journal

Journal ID (nlm-ta): Int J Mol Sci

Journal ID (iso-abbrev): Int J Mol Sci

Journal ID (publisher-id): ijms

Title: International Journal of Molecular Sciences

Publisher: MDPI

ISSN (Electronic): 1422-0067

Publication date (Electronic): 30 April 2019

Publication date Collection: May 2019

Volume: 20

Issue: 9

Electronic Location Identifier: 2138

Affiliations

[1 ]Department of Nephrology and Medical Intensive Care, Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany; kai-uwe.eckardt@ 123456charite.de

[2 ]Max-Delbrück Center for Molecular Medicine in the Helmholtz Association, 13125 Berlin, Germany

[3 ]Experimental and Clinical Research Center, a joint cooperation of Max-Delbrück Center for Molecular Medicine and Charité-Universitätsmedizin Berlin, 13125 Berlin, Germany

[4 ]Berlin Institute of Health (BIH), 10178 Berlin, Germany

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[* ]Correspondence: laura-katharina.sievers@ 123456charite.de

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Laura Katharina Sievers https://orcid.org/0000-0002-4677-5181

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Publisher ID: ijms-20-02138

DOI: 10.3390/ijms20092138

PMC ID: 6539752

PubMed ID: 31052201

SO-VID: 02af5382-03e2-47d0-a528-4abf14fe1696

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Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

Molecular Mechanisms of Kidney Injury and Repair in Arterial Hypertension

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Abstract

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Karger: Nephrology

Most cited references 53

Inflammation, immunity, and hypertensive end-organ damage.

Endovascular ultrasound renal denervation to treat hypertension (RADIANCE-HTN SOLO): a multicentre, international, single-blind, randomised, sham-controlled trial

T regulatory lymphocytes prevent angiotensin II-induced hypertension and vascular injury.

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