Emerging evidence has highlighted the pivotal role of microvasculature injury in the development and progression of renal fibrosis. Angiopoietins (Angs) are a family of vascular growth factors that bind to the endothelial cell specific tyrosine kinase receptor Tie2. Ang-1 and Ang-3 are agonists while Ang-2 and Ang-4 are antagonists for Tie2. Ang-1/Tie2 signaling is critical for regulating blood vessel development and modulating vascular response after injury. Although dysregulation of vascular endothelial growth factor (VEGF) signaling has been well studied in renal pathologies, much less is known about the role of the Ang-1/Tie2 pathway in renal interstitial fibrosis.
We investigated the impact of site-directed expression of native Ang-1 on the renal fibrogenic process and peritubular capillary network by exploiting a conditional transgenic mouse system [Pax8-rtTA/(TetO)7 Ang-1] that allows increased tubular Ang-1 production in adult mice.
Using a murine unilateral ureteral obstruction (UUO) fibrosis model, we demonstrate that targeted Ang-1 overexpression attenuates myofibroblast activation and interstitial collagen I accumulation, inhibits the upregulation of transforming growth factor β1 and subsequent phosphorylation of Smad 2/3, dampens renal inflammation, and stimulates the growth of peritubular capillaries in the obstructed kidney.
Our results suggest that Ang-1 is a potential therapeutic agent for targeting microvasculature injury in renal fibrosis without compromising the physiologically normal vasculature in humans.
We will continue to investigate how Ang-1 affects renal fibrosis in a variety of kidney diseases by utilizing inducible glomerular or renal-tubular specific transgene system, cell biology, biochemistry and state-of-the-art imaging techniques.