Sex differences in angiotensin II-induced hypertension and kidney injury: role of AT1a receptors in the proximal tubule of the kidney

Leite, Ana Paula de Oliveira; Li, Xiao C.; Hassan, Rumana; Zheng, Xiaowen; Alexander, Barbara T.; Casarini, Dulce Elena; Zhuo, Jia L.

doi:10.1042/cs20201574

Cited by 11 publications

(43 citation statements)

References 48 publications

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“…In a similar nitric oxide inhibition-induced hypertension model in rats, blood pressures between male and female groups were not significantly different until after Day 15 [23]. In a murine A2HTN model where angiotensin II was administered at a rate of 1.5 mg/kg/day, blood pressures were not significantly different throughout the 14-day study [24]. In past studies, we have observed compensatory renal lymphangiogenesis in both male and female LHTN and A2HTN mice, and renal lymphatic vessel density was not significantly altered between sexes [9,11].…”

Section: Discussionmentioning

confidence: 84%

A Kidney-Targeted Nanoparticle to Augment Renal Lymphatic Density Decreases Blood Pressure in Hypertensive Mice

et al. 2021

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Chronic interstitial inflammation and renal infiltration of activated immune cells play an integral role in hypertension. Lymphatics regulate inflammation through clearance of immune cells and excess interstitial fluid. Previously, we demonstrated increasing renal lymphangiogenesis prevents hypertension in mice. We hypothesized that targeted nanoparticle delivery of vascular endothelial growth factor-C (VEGF-C) to the kidney would induce renal lymphangiogenesis, lowering blood pressure in hypertensive mice. A kidney-targeting nanoparticle was loaded with a VEGF receptor-3-specific form of VEGF-C and injected into mice with angiotensin II-induced hypertension or LNAME-induced hypertension every 3 days. Nanoparticle-treated mice exhibited increased renal lymphatic vessel density and width compared to hypertensive mice injected with VEGF-C alone. Nanoparticle-treated mice exhibited decreased systolic blood pressure, decreased pro-inflammatory renal immune cells, and increased urinary fractional excretion of sodium. Our findings demonstrate that pharmacologically expanding renal lymphatics decreases blood pressure and is associated with favorable alterations in renal immune cells and increased sodium excretion.

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Section: Discussionmentioning

confidence: 84%

A Kidney-Targeted Nanoparticle to Augment Renal Lymphatic Density Decreases Blood Pressure in Hypertensive Mice

et al. 2021

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“…By contrast, deletion of AT 1a receptors in all tissues of the body led to an approximately 30 ± 5 mmHg lower systolic, diastolic, and mean arterial blood pressure in global Agtr1a -/- mice [ 11 , 16 , 28 , 55 ]. No significant sex differences in this basal blood pressure phenotype were observed in either global Agtr1a -/- or proximal tubule-specific PT- Agtr1a -/- mice [ 12 , 28 ]. The blood pressure-lowering effect in PT- Agtr1a -/- mice was associated with significant diuretic and natriuretic responses and increases in the basal glomerular filtration rate as well as the pressure-natriuresis response due to the inhibition of Na + and fluid reabsorption in the proximal tubules ( Figure 2 ) [ 28 , 104 , 105 ].…”

Section: At 1 (At 1a ) Receptor...mentioning

confidence: 99%

“…The development of Ang II-induced hypertension has been extensively studied in different animal models with AT 1 (AT 1a ) receptors playing the fundamental role [ 12 , 27 , 71 , 97 , 104 ]. AT 1 (AT 1a ) receptors are expressed widely, although to different levels, in the brain, adrenal glands, and cardiovascular and kidney tissues; thus, the mechanisms underlying Ang II-induced hypertension are expected to involve different tissues or pathways [ 16 , 39 ].…”

Section: At 1 (At 1a ) Receptor...mentioning

confidence: 99%

“…AT 1 (AT 1a ) receptors are expressed widely, although to different levels, in the brain, adrenal glands, and cardiovascular and kidney tissues; thus, the mechanisms underlying Ang II-induced hypertension are expected to involve different tissues or pathways [ 16 , 39 ]. We and others have recently determined the direct contributions of intratubular Ang II via AT 1 (AT 1a ) receptors in the proximal tubules in the development of Ang II-induced hypertension by comparing global, kidney-, and proximal tubule-specific Agtr1a -/- mice [ 10 , 11 , 12 , 16 , 27 , 28 , 97 , 104 ]. As discussed previously in the cross-kidney transplantation study, Crowley et al reported that kidney AT 1 (AT 1a ) receptors played virtually equivalent roles in AT 1 receptor actions in the kidney and in extrarenal tissues to determining the level of blood pressure and the development of Ang II-infused hypertension [ 10 , 96 ].…”

Section: At 1 (At 1a ) Receptor...mentioning

confidence: 99%

“…Recently, the XIII International Symposium on Vasoactive Peptides was held on 15–17 October 2021, which celebrated recent advances in studying the roles of vasoactive peptides, especially the renin–angiotensin system, in cardiovascular, neural, kidney, and blood pressure control, inflammation and the COVID-19 pandemic. Based on a lecture given at this symposium, the objective of this article is to briefly review and discuss recent studies using unique mouse models with proximal tubule-specific deletion (knockout) of Ang II type 1a receptors (AT 1a ) or its major downstream target protein, the Na + /H + exchanger 3 (NHE3) in the kidney [ 12 , 13 , 14 , 15 , 16 ]. These studies have revealed important roles of AT 1a receptors, acting alone or via NHE3, in the proximal tubules in maintaining basal blood pressure homeostasis, the pressure-natriuresis response, and the development of Ang II-induced hypertension.…”

Section: Introductionmentioning

confidence: 99%

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Angiotensin II and AT1a Receptors in the Proximal Tubules of the Kidney: New Roles in Blood Pressure Control and Hypertension

Leite

Nwia

et al. 2022

IJMS

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Contrary to public perception, hypertension remains one of the most important public health problems in the United States, affecting 46% of adults with increased risk for heart attack, stroke, and kidney diseases. The mechanisms underlying poorly controlled hypertension remain incompletely understood. Recent development in the Cre/LoxP approach to study gain or loss of function of a particular gene has significantly helped advance our new insights into the role of proximal tubule angiotensin II (Ang II) and its AT1 (AT1a) receptors in basal blood pressure control and the development of Ang II-induced hypertension. This novel approach has provided us and others with an important tool to generate novel mouse models with proximal tubule-specific loss (deletion) or gain of the function (overexpression). The objective of this invited review article is to review and discuss recent findings using novel genetically modifying proximal tubule-specific mouse models. These new studies have consistently demonstrated that deletion of AT1 (AT1a) receptors or its direct downstream target Na+/H+ exchanger 3 (NHE3) selectively in the proximal tubules of the kidney lowers basal blood pressure, increases the pressure-natriuresis response, and induces natriuretic responses, whereas overexpression of an intracellular Ang II fusion protein or AT1 (AT1a) receptors selectively in the proximal tubules increases proximal tubule Na+ reabsorption, impairs the pressure-natriuresis response, and elevates blood pressure. Furthermore, the development of Ang II-induced hypertension by systemic Ang II infusion or by proximal tubule-specific overexpression of an intracellular Ang II fusion protein was attenuated in mutant mice with proximal tubule-specific deletion of AT1 (AT1a) receptors or NHE3. Thus, these recent studies provide evidence for and new insights into the important roles of intratubular Ang II via AT1 (AT1a) receptors and NHE3 in the proximal tubules in maintaining basal blood pressure homeostasis and the development of Ang II-induced hypertension.

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Macrophage Dectin-1 mediates Ang II renal injury through neutrophil migration and TGF-β1 secretion

Huang

Yun

et al. 2023

Cell. Mol. Life Sci.

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Macrophage activation has been shown to play an essential role in renal fibrosis and dysfunction in hypertensive chronic kidney disease. Dectin-1 is a pattern recognition receptor that is also involved in chronic noninfectious diseases through immune activation. However, the role of Dectin-1 in Ang II-induced renal failure is still unknown. In this study, we found that Dectin-1 expression on CD68 + macrophages was significantly elevated in the kidney after Ang II infusion. We assessed the effect of Dectin-1 on hypertensive renal injury using Dectin-1-deficient mice infused by Angiotensin II (Ang II) at 1000 ng/kg/min for 4 weeks. Ang II-induced renal dysfunction, interstitial fibrosis, and immune activation were significantly attenuated in Dectin-1-deficient mice. A Dectin-1 neutralizing antibody and Syk inhibitor (R406) were used to examine the effect and mechanism of Dectin-1/Syk signaling axle on cytokine secretion and renal fibrosis in culturing cells. Blocking Dectin-1 or inhibiting Syk significantly reduced the expression and secretion of chemokines in RAW264.7 macrophages. The in vitro data showed that the increase in TGF-β1 in macrophages enhanced the binding of P65 and its target promotor via the Ang II-induced Dectin-1/Syk pathway. Secreted TGF-β1 caused renal fibrosis in kidney cells through Smad3 activation. Thus, macrophage Dectin-1 may be involved in the activation of neutrophil migration and TGF-β1 secretion, thereby promoting kidney fibrosis and dysfunction. Graphical Abstract

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Sex differences in angiotensin II-induced hypertension and kidney injury: role of AT1a receptors in the proximal tubule of the kidney

Cited by 11 publications

References 48 publications

A Kidney-Targeted Nanoparticle to Augment Renal Lymphatic Density Decreases Blood Pressure in Hypertensive Mice

A Kidney-Targeted Nanoparticle to Augment Renal Lymphatic Density Decreases Blood Pressure in Hypertensive Mice

Angiotensin II and AT1a Receptors in the Proximal Tubules of the Kidney: New Roles in Blood Pressure Control and Hypertension

Macrophage Dectin-1 mediates Ang II renal injury through neutrophil migration and TGF-β1 secretion

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