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Mutations in natriuretic peptide receptor 2 (Npr2) gene cause a rare form of short-limbed dwarfism, but its physiological effects have not been well studied. Human and mouse genetic data suggest that Npr2 in the kidney plays a role in salt homeostasis. Herein, we described anatomic changes within renal papilla of Npr2 knockout (Npr2 -/- ) mice. Dramatic reduction was found in diuresis, and albuminuria was evident after administration of 1% NaCl in drinking water in Npr2 -/- and heterozygous (Npr2 +/- ) mice compared with their wild-type (Npr2 +/+ ) littermates. There was indication of renal epithelial damage accompanied by high numbers of red blood cells and inflammatory cells (macrophage surface glycoproteins binding to galectin-3) and an increase of renal epithelial damage marker (T-cell Ig and mucin domain 1) in Npr2 -/- mice. Addition of 1% NaCl tended to increase apoptotic cells (cleaved caspase 3) in the renal papilla of Npr2 -/- mice. In vitro, genetic silencing of the Npr2 abolished protective effects of C-type natriuretic peptide, a ligand for Npr2, against death of M-1 kidney epithelial cells exposed to 360 mmol/L NaCl. Finally, significantly lower levels of expression of the NPR2 protein were detected in renal samples of hypertensive compared with normotensive human subjects. Taken together, these findings suggest that Npr2 is essential to protect renal epithelial cells from high concentrations of salt and prevent kidney injury., (Copyright © 2019 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

The balance between adaptive and innate immunity in kidney damage in salt-dependent hypertension is unclear. We investigated early renal dysfunction and the influence of Axl, a receptor tyrosine kinase, on innate immune response in hypertensive kidney in mice with lymphocyte deficiency (Rag1 -/- ). The data suggest that increased presence of CD11b + myeloid cells in the medulla might explain intensified salt and water retention as well as initial hypertensive response in Rag1 -/- mice. Global deletion of Axl on Rag1 -/- background reversed kidney dysfunction and accumulation of myeloid cells in the kidney medulla. Chimeric mice that lack Axl in innate immune cells (in the absence of lymphocytes) significantly improved kidney function and abolished early hypertensive response. The bioinformatics analyses of Axl-related gene-gene interaction networks established tissue-specific variation in regulatory pathways. It was confirmed that complement C3 is important for Axl-mediated interactions between myeloid and vascular cells in hypertensive kidney. In summary, innate immunity is crucial for renal dysfunction in early hypertension, and is highly influenced by the presence of Axl., (Copyright © 2018 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Objective: Survival of immune and nonimmune cells relies on Axl, a receptor tyrosine kinase, which is implicated in hypertension. Activated T lymphocytes are involved in regulation of high blood pressure. The goal of the study was to investigate the role of Axl in T-lymphocyte functions and its contribution to salt-dependent hypertension., Approach and Results: We report increased apoptosis in peripheral blood from Axl(-/-) mice because of lower numbers of white blood cells mostly lymphocytes. In vitro studies showed modest reduction in interferon gamma production in Axl(-/-) type 1 T helper cells. Axl did not affect basic proliferation capacity or production of interleukin 4 in Axl(-/-) type 2 T helper cells. However, competitive repopulation of Axl(-/-) bone marrow or adoptive transfer of Axl(-/-) CD4(+) T cells to Rag1(-/-) mice showed robust effect of Axl on T lymphocyte expansion in vivo. Adoptive transfer of Axl(-/-) CD4(+) T cells was protective in a later phase of deoxycorticosterone-acetate and salt hypertension. Reduced numbers of CD4(+) T cells in circulation and in perivascular adventitia decreased vascular remodeling and increased vascular apoptosis in the late phase of hypertension., Conclusions: These findings suggest that Axl is critical for survival of T lymphocytes, especially during vascular remodeling in hypertension., (© 2016 American Heart Association, Inc.)

The Gas6/Axl pathway regulates many cell functions and is implicated in hypertension. In this study, we aimed to investigate the role of Axl in immune cells on initiation and progression of salt-dependent hypertension. Deoxycorticosterone acetate (75 mg/60 days release)-salt hypertension was induced for 1 week or 6 weeks in Axl chimeras generated by bone marrow transplant to restrict Axl deficiency to hematopoietic or nonhematopoietic compartments. Depletion of Axl in hematopoietic cells (Axl(-/-) →Axl(+/+)) reduced (133 ± 2 mm Hg) increase in systolic blood pressure compared with other Axl chimeras (≈150 mm Hg) 1 week after deoxycorticosterone acetate-salt. Urine protein and renal oxidative stress were lowest in Axl(-/-) →Axl(+/+) at 1 week after deoxycorticosterone acetate-salt. Compensatory increase in Gas6 in kidneys of recipient Axl(-/-) may affect kidney function and blood pressure in early phase of hypertension. Flow cytometry on kidneys from Axl(-/-) →Axl(+/+) showed increase in total leukocytes, B, and dendritic cells and decrease in macrophages compared with Axl(+/+) →Axl(+/+). These immune changes were associated with decrease in proinflammatory gene expression, in particular interferon γ. Systolic blood pressure returned to baseline in Axl(-/-) →Axl(+/+) and Axl(-/-) →Axl(-/-) but remained increased in Axl(+/+) →Axl(+/+) and Axl(+/+) →Axl(-/-) chimeras after 6 weeks of deoxycorticosterone acetate-salt. Vascular apoptosis was increased in the global Axl(-/-) chimeras in the late phase of hypertension. In summary, we found that expression of Axl in hematopoietic cells is critical for kidney pathology in early phase of salt-dependent hypertension. However, Axl in both hematopoietic and nonhematopoietic lineages contributes to the late phase of hypertension.

Axl, a receptor tyrosine kinase, was recently identified as a novel candidate gene in a genetic model of salt-sensitive hypertension (Sabra rat). Our group first reported that Axl plays a significant role in vascular remodeling in response to injury. Here we investigated the role of Axl in the pathogenesis of hypertension in a deoxycorticosterone acetate (DOCA)-salt model. Hypertension was induced in Axl wild-type (Axl(+/+)) mice and Axl-deficient (Axl(-/-)) mice by uninephrectomy and DOCA-salt for 6 weeks. Controls were uninephrectomized and received tap water and regular chow ad libitum. DOCA-salt treatment increased systolic blood pressure by 25 mm Hg in both genotypes after 1 week. Systolic blood pressure remained significantly elevated in Axl(+/+) DOCA, whereas systolic blood pressure levels in Axl(-/-) DOCA mice were the same as controls at 6 weeks. DOCA-salt increased relative kidney weight and glomerular hypertrophy by 40% compared with controls in both genotypes. Consistent with levels of systolic blood pressure, endothelium-dependent vasorelaxation was impaired in Axl(+/+) DOCA mice compared with Axl(+/+) controls, whereas in Axl(-/-) DOCA mice relaxation responses were similar to Axl(-/-) controls. In addition, endothelium-independent vasorelaxation was improved in Axl(-/-) DOCA mice compared with Axl(+/+) DOCA mice. Nitrotyrosine and phospho-Akt immunoreactivity was significantly reduced in arteries from Axl(-/-) DOCA mice compared with Axl(+/+) DOCA mice. The remodeling index of the mesenteric artery (media:lumen ratio) was significantly increased in Axl(+/+) DOCA mice compared with Axl(-/-) DOCA mice. Finally, increased vascular apoptosis in the Axl(-/-) DOCA mice suggests a likely mechanism for Axl-dependent effects on hypertension. These data strengthen the pathogenic role for Axl in salt-sensitive hypertension.

Omapatrilat inhibits neutral endopeptidase (NEP) and angiotensin-converting enzyme (ACE). We compared the effects of omapatrilat (40 mg/kg/day, p.o.) to fosinopril (40 mg/kg/day, p.o.) on flow-induced vascular remodeling in New Zealand genetically hypertensive (GH) rats. Both drugs equally reduced blood pressure (BP) initially, but systolic BP and pulse pressure were reduced more by omapatrilat after 1 week. Carotid remodeling was induced by partial ligation of the left common carotid artery (LCA). There was little remodeling in untreated GH rats - measured as outer diameter to body weight (OD/BW vs. before ligation): 97 +/- 1% of initial LCA (low flow) and 107 +/- 3% of initial right common carotid artery (RCA, high flow). In contrast, OD/BW increased to 118 +/- 5% (p < 0.05) of initial RCA after omapatrilat versus 108 +/- 2% (p = 0.96) after fosinopril. The major change was increased RCA lumen area which was significantly larger in omapatrilat-treated animals (127% vs. control) than fosinopril-treated animals (103% vs. control). The increase in outward remodeling after omapatrilat treatment correlated weakly with vascular cGMP levels and decreased systolic BP. The results suggest that dual inhibition of NEP/ACE may have greater effects than ACE inhibition alone on vessel remodeling in hypertension., (Copyright 2004 S. Karger AG, Basel)

Tetrindole (a tetracyclic antidepressant, reversible MAO inhibitor of the A type) and desipramine (a tricyclic antidepressant, nonselective inhibitor of the reverse catecholamine trapping) produce opposite hemodynamic effects in stroke-prone hypertensive rats (SHR-SP): tetrindole reduced, whereas desipramine increased, the heart rate and arterial pressure. Under the acute immobilization stress conditions in SHR-SP, tetrindole inhibited development of the post-stressor tachycardia, while desipramine did not change the heart rate and increased the arterial pressure.

A study on hybrids from reciprocal crossing of the SHR-SP and the WKY has shown that Y-chromosome and mitochondrial DNA the affect development of the spontaneous hypertension. The Y-chromosome takes part in disorders of baroreceptive sensitivity in phenylnephrine assay associated with hypertension. Although our findings suggest that structural remodelling of peripheral vascular resistance and an increase in noradrenaline-dependent vasocostriction is genetically determined in hypertensive rats, we could not corroborate the role of the Y-chromosome and mitochondrial DNA in the process. A difference was shown between male and female SHR-SP in the level of arterial pressure and in development of the vascular structure changes.