Activation of Angiopoietin-Tie2 Signaling Protects the Kidney from Ischemic Injury by Modulation of Endothelial-Specific Pathways.

SIGNIFICANCE STATEMENT: Ischemia-reperfusion AKI (IR-AKI) is common and causes significant morbidity. Effective treatments are lacking. However, preclinical studies suggest that inhibition of angiopoietin-Tie2 vascular signaling promotes injury, whereas activation of Tie2 is protective. We show that kidney ischemia leads to increased levels of the endothelial-specific phosphatase vascular endothelial protein tyrosine phosphatase (VE-PTP; PTPRB), which inactivates Tie2. Activation of Tie2 through VE-PTP deletion, or delivery of a novel angiopoietin mimetic (Hepta-ANG1), abrogated IR-AKI in mice. Single-cell RNAseq analysis showed Tie2 activation promotes increased Entpd1 expression, downregulation of FOXO1 target genes in the kidney vasculature, and emergence of a new subpopulation of glomerular endothelial cells. Our data provide a molecular basis and identify a candidate therapeutic to improve endothelial integrity and kidney function after IR-AKI. BACKGROUND: Ischemia-reperfusion AKI (IR-AKI) is estimated to affect 2%-7% of all hospitalized patients. The significant morbidity and mortality associated with AKI indicates urgent need for effective treatments. Previous studies have shown activation of the vascular angiopoietin-Tie2 tyrosine kinase signaling pathway abrogates ischemia-reperfusion injury (IRI). We extended previous studies to (1) determine the molecular mechanism(s) underlying kidney injury and protection related to decreased or increased activation of Tie2, respectively, and (2) to test the hypothesis that deletion of the Tie2 inhibitory phosphatase vascular endothelial protein tyrosine phosphatase (VE-PTP) or injection of a new angiopoietin mimetic protects the kidney from IRI by common molecular mechanism(s). METHODS: Bilateral IR-AKI was performed in VE-PTP wild-type or knockout mice and in C57BL/6J mice treated with Hepta-ANG1 or vehicle. Histologic, immunostaining, and single-cell RNA sequencing analyses were performed. RESULTS: The phosphatase VE-PTP, which negatively regulates the angiopoietin-Tie2 pathway, was upregulated in kidney endothelial cells after IRI, and genetic deletion of VE-PTP in mice protected the kidney from IR-AKI. Injection of Hepta-ANG1 potently activated Tie2 and protected the mouse kidney from IRI. Single-cell RNAseq analysis of kidneys from Hepta-ANG1-treated and vehicle-treated mice identified endothelial-specific gene signatures and emergence of a new glomerular endothelial subpopulation associated with improved kidney function. Overlap was found between endothelial-specific genes upregulated by Hepta-ANG1 treatment and those downregulated in HUVECs with constitutive FOXO1 activation, including Entpd1 / ENTPD1 that modulates purinergic receptor signaling. CONCLUSIONS: Our data support a key role of the endothelium in the development of IR-AKI, introduce Hepta-ANG1 as a putative new therapeutic biologic, and report a model to explain how IRI reduces Tie2 signaling and how Tie2 activation protects the kidney. PODCAST: This article contains a podcast at https://dts.podtrac.com/redirect.mp3/www.asn-online.org/media/podcast/JASN/2023_05_23_JSN_Ang_EP23_052323.mp3.

Dialytic interval and the timing of electrocardiographic screening for subcutaneous cardioverter-defibrillator placement in chronic hemodialysis patients.

BACKGROUND: Hemodialysis (HD) patients have a high risk of sudden death but limited vascular access and high complication rates from transvenous implantable cardioverter-defibrillators (ICDs). Subcutaneous ICDs (S-ICD) may be an alternative, but dynamic ECG changes may result in inappropriate shocks. This study aims to define the screen failure rate for S-ICD in patients pre- and post-HD. METHODS: ECG waveforms were obtained using electrodes mimicking the S-ICD sensing vectors in an unselected test group of chronic HD patients and a control group of ICD-eligible non-dialysis patients. Participants passed screening if their QRS and T-waves fit within the screening template in supine and standing positions in any lead. Test group participants were screened before and after HD and control group patients were screened at two separate time points. HD patients were stratified into the four following groups: (A) passed screening before and after HD, (B) failed screening before but passed after HD, (C) passed screening before but failed after HD, and (D) failed screening before and after HD. Patients in group A passed the screening for ICD implantation, and patients in groups B, C, and D failed the screening for ICD implantation. Control patients were similarly classified by pass/fail status at the two assessment points. RESULTS: Of the 76 patients enrolled, 51 were HD patients and 25 were controls. Of the 51 HD patients, 43 (84%) were in group A, four participants (8%) were in group B, one (2%) was in group C, and three participants (6%) were in group D. There were no differences in any of the clinical or demographic variables between the pass and fail test HD groups. None of the 25 controls failed the screening at either time point (p = 0.047 vs HD patients). CONCLUSIONS: Overall, HD patients were more likely to fail S-ICD screening compared to non-HD patients (16 v 0%, p = 0.047) and are more likely to do so prior to HD. Patients on HD should be screened at multiple time points around the dialytic interval to reduce the risk of inappropriate shocks.

A case of symptomatic deep vein thrombosis mimicking occlusive peripheral arterial disease.

Peripheral arterial disease (PAD) and acute deep vein thrombosis (DVT) can both result in similar calf pain presentation. Treatment modalities depend on the etiology of the pain. We present the case of a 63-year-old female with left lower extremity pain and describe our eventual diagnosis of DVT as the cause of her symptoms.