Targeting TIE2 Signaling Shows Promise in Preventing Kidney Fibrosis

A new preclinical study suggests that activating the endothelial receptor TIE2 could offer a novel therapeutic approach to chronic kidney disease (CKD) by preserving capillary integrity and halting fibrosis progression.

Published in the Journal of Clinical Investigation, the study presents compelling evidence that vascular protection via TIE2 activation significantly mitigates renal injury in experimental CKD models.

CKD, a condition affecting over 800 million people globally, is driven in part by capillary rarefaction and tubulointerstitial fibrosis. Although endothelial dysfunction has been observed in the disease’s progression, its exact contribution has remained elusive. The current study sheds light on this relationship by focusing on TIE2, a tyrosine kinase receptor predominantly expressed on endothelial cells and regulated by angiopoietin ligands ANGPT1 and ANGPT2.

In healthy conditions, ANGPT1 maintains vascular quiescence by activating TIE2. In contrast, ANGPT2, which is elevated in CKD patients, acts as a context-dependent antagonist of TIE2 signaling. This study introduces ABTAA—an engineered antibody that clusters endogenous ANGPT2 to activate TIE2—as a strategy to restore endothelial stability and prevent fibrosis.

Using a well-established murine model of CKD (unilateral ureteral obstruction, or UUO), the researchers compared pharmacologic TIE2 activation using ABTAA with genetic approaches. Mice receiving ABTAA or engineered to delete the TIE2-inhibiting phosphatase Veptp (thereby enhancing TIE2 signaling) showed preserved capillary density, reduced tubular injury, and significantly attenuated fibrosis. Conversely, mice with endothelial-specific deletion of Tie2 exhibited exacerbated kidney damage, reinforcing the receptor's protective role.

A critical mechanistic insight from the study involves the growth factor PDGFB, known for activating perivascular mesenchymal cells that drive fibrosis. While previous theories proposed endothelial-to-mesenchymal transition (EndoMT) as a source of fibrosis, this study refutes that. Instead, it finds that endothelial dysfunction increases PDGFB expression in tubular epithelial cells, not endothelial cells—a process that is directly inhibited by TIE2 activation.

Even when ABTAA treatment was delayed until after injury onset, the intervention still significantly reduced fibrosis and PDGFB expression, though capillary density was no longer preserved—suggesting early vascular protection is key to maintaining full microvascular integrity.

Bulk RNA sequencing confirmed that TIE2 activation dampens transcriptional programs associated with extracellular matrix remodeling, oxidative stress, and tubular damage. Importantly, gene expression patterns in ABTAA-treated mice more closely resembled those of healthy controls than those in untreated UUO mice.

The authors also cross-referenced human datasets, showing that key markers disrupted in the murine UUO model—such as increased ANGPT2 and PDGFB, and decreased ANGPT1—are similarly altered in patients with CKD or transplant-associated renal dysfunction.

What sets ABTAA apart from previous TIE2-targeting approaches is its context-dependent activity: it only activates TIE2 in environments with elevated ANGPT2, such as injured kidneys, minimizing the risk of systemic vascular side effects. This localized mechanism could make it a safer alternative to global TIE2 agonism or VEPTP inhibition.

Although the study was limited to a single CKD model, its findings align with prior reports demonstrating the therapeutic benefit of ANGPT1 mimetics and ANGPT2 inhibitors across various models of renal injury. The authors advocate for advancing ABTAA into clinical trials to assess its potential as a targeted therapy for CKD.

As chronic kidney disease continues its climb as a leading global cause of mortality, vascular-focused interventions like TIE2 activation may offer a new frontier in halting its progression.