Impact of Angiopoietin-2 on Kidney Diseases

Abstract

Background: Angiopoietins (Ang) are essential angiogenic factors involved in angiogenesis, vascular maturation, and inflammation. The most studied angiopoietins, angiopoietin-1 (Ang-1) and angiopoietin-2 (Ang-2), behave antagonistically to each other in vivo to sustain vascular endothelium homeostasis. While Ang-1 typically acts as the endothelium-protective mediator, its context-dependent antagonist Ang-2 can promote endothelium permeability and vascular destabilization, hence contributing to a poor outcome in vascular diseases via endothelial injury, vascular dysfunction, and microinflammation. The pathogenesis of kidney diseases is associated with endothelial dysfunction and chronic inflammation in renal diseases.

Summary: Several preclinical studies report overexpression of Ang-2 in renal tissues of certain kidney disease models; additionally, clinical studies show increased levels of circulating Ang-2 in the course of chronic kidney disease, implying that Ang-2 may serve as a useful biomarker in these patients. However, the exact mechanisms of Ang-2 action in renal diseases remain unclear.

Key messages: We summarized the recent findings on Ang-2 in kidney diseases, including preclinical studies and clinical studies, aiming to provide a systematic understanding of the role of Ang-2 in these diseases.

Keywords: Angiogenesis; Angiopoietin-2; Kidney diseases.

Fig. 1. a, b

The process of Ang-2 from generation and function. The figure depicts that Ang-2 is partly derived from ECs of blood vessels. Ang-2 is rapidly released into circulation upon stimuli of inflammation or ischemia/hypoxia. Ang-2 competes for the TIE-2 receptor with Ang-1 and can also bind to activated integrin β1 to elicit biological function. a Ang-2 expression in kidney tissue was shown to be significantly upregulated in preclinical kidney disease models. b Circulating Ang-2 levels are markedly increased in patients with various kidney diseases based on preclinical studies and clinical studies. Ang-2, angiopoietin-2; Ang-1, angiopoietin-1; AKI, acute kidney injury; ADPKD, autosomal dominant polycystic kidney disease; GCN, chronic glomerulonephritis; CKD, chronic kidney disease; DN, diabetic nephropathy; DM, diabetes mellitus; ECs, endothelial cells; GN, glomerulonephritis; LN, lupus nephritis.

Fig. 2.

Ang-2 immunostaining in normal kidney biopsy. Immunohistochemical expression of Ang-2 in normal human kidney tissue. Brown indicates Ang-2 positive. Physiological Ang-2 expression in tubular epithelial cells (arrow a shows strong Ang-2 positivity of the brush border, and arrow c shows moderate cytoplasmatic Ang-2 positivity) next to a focal weak Ang-2 positivity of glomerular parietal epithelial cells (arrow b shows Bowman’s capsule) may be observed. No specific Ang-2 staining can be detected in arteries (arrows d, e), glomerular capillaries (arrow f), or interstitium (arrow g). Immunohistochemistry was performed on paraffin-embedded renal biopsy samples from a healthy biopsy in the University Medical Centre Mannheim using a primary antibody (Angiopoietin 2 Polyclonal Antibody [DF6137]). Image acquisition was done using a PreciPoint scanning microscope (using objective ×40/0.65 NA) and MicroPoint software (v.2016-02-05; PreciPoint, Freising, Germany).