Role of Axl in Early Kidney Inflammation and Progression of Salt-Dependent Hypertension

Batchu, Sri Nagarjun; Hughson, Angie; Gerloff, Janice; Fowell, Deborah J.; Korshunov, Vyacheslav A.

doi:10.1161/hypertensionaha.113.01382

Cited by 24 publications

(32 citation statements)

References 25 publications

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“…Similar to our report in Axl chimeras 15 , we found reduction in arterial expression of IFN-γ (and Th1-dependent pathways) in Axl −/− mice after 6 weeks of DOCA-salt (not shown). We performed adoptive transfers of CD4 + T cells from Axl +/+ or Axl −/− to Rag1 −/− mice and compared BP changes after DOCA-salt to that in Rag1 −/− injected with PBS (PBS→Rag1 −/− ) or Axl +/+ mice (Fig.…”

Section: Resultssupporting

confidence: 91%

“…Specifically, our group showed that Axl-dependent signals control vascular smooth muscle cells survival and promote vascular remodeling after 6 weeks of DOCA-salt 13 . We recently reported that Axl expression in bone marrow (BM)-derived cells is responsible for early and late phases of DOCA-salt hypertension 15 . Adaptive immune cells such as T lymphocytes contribute to vascular dysfunction and DOCA-salt hypertension 16 .…”

Section: Introductionmentioning

confidence: 99%

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Role of Axl in T-Lymphocyte Survival in Salt-Dependent Hypertension

Batchu

Hughson

Wadosky

et al. 2016

ATVB

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Objective Survival of immune and non-immune 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 For the first time we report increased apoptosis in peripheral blood from Axl−/− mice due to lower numbers of white blood cells mostly lymphocytes. In vitro studies showed modest reduction in interferon gamma production in Axl−/− Th1 cells. Axl did not affect basic proliferation capacity or production of interleukin 4 in Axl−/− Th2 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 lymphocytes 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.

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Section: Resultssupporting

confidence: 91%

Section: Introductionmentioning

confidence: 99%

Role of Axl in T-Lymphocyte Survival in Salt-Dependent Hypertension

Batchu

Hughson

Wadosky

et al. 2016

ATVB

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“…Renal Axl expression having a protective function in kidney pathology is also consistent with a recent report examining the role of haematopoietic and non-haematopoietic Axl in DOCA salt-induced hypertension and kidney dysfunction [29]. This study demonstrated that while haematopoietic Axl had a pathological role in the model, non-haematopoietic Axl protected against renal reactive oxygen species production [29].…”

Section: Discussionsupporting

confidence: 91%

Axl Tyrosine Kinase Protects against Tubulo-Interstitial Apoptosis and Progression of Renal Failure in a Murine Model of Chronic Kidney Disease and Hyperphosphataemia

et al. 2014

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Chronic kidney disease (CKD) is defined as the progressive loss of renal function often involving glomerular, tubulo-interstitial and vascular pathology. CKD is associated with vascular calcification; the extent of which predicts morbidity and mortality. However, the molecular regulation of these events and the progression of chronic kidney disease are not fully elucidated. To investigate the function of Axl receptor tyrosine kinase in CKD we performed a sub-total nephrectomy and fed high phosphate (1%) diet to Axl+/+ and Axl−/− mice. Plasma Gas6 (Axl' ligand), renal Axl expression and downstream Akt signalling were all significantly up-regulated in Axl+/+ mice following renal mass reduction and high phosphate diet, compared to age-matched controls. Axl−/− mice had significantly enhanced uraemia, reduced bodyweight and significantly reduced survival following sub-total nephrectomy and high phosphate diet compared to Axl+/+ mice; only 45% of Axl−/− mice survived to 14 weeks post-surgery compared to 87% of Axl+/+ mice. Histological analysis of kidney remnants revealed no effect of loss of Axl on glomerular hypertrophy, calcification or renal sclerosis but identified significantly increased tubulo-interstitial apoptosis in Axl−/− mice. Vascular calcification was not induced in Axl+/+ or Axl−/− mice in the time frame we were able to examine. In conclusion, we identify the up-regulation of Gas6/Axl signalling as a protective mechanism which reduces tubulo-interstitial apoptosis and slows progression to end-stage renal failure in the murine nephrectomy and high phosphate diet model of CKD.

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“…Data analyses were done using a web-based suite at SABiosciences (Qiagen). We used the curated InnateDB resource for pathway analyses as we have previously described (1,8).…”

Section: Methodsmentioning

confidence: 99%