Endostatin in Renal and Cardiovascular Diseases

Abstract

Endostatin, a protein derived from the cleavage of collagen XVIII by the action of proteases, is an endogenous inhibitor known for its ability to inhibit proliferation and migration of endothelial cells, angiogenesis, and tumor growth. Angiogenesis is defined as the formation of new blood vessels from pre-existing vasculature, which is crucial in many physiological processes, such as embryogenesis, tissue regeneration, and neoplasia.

Summary: Increasing evidence shows that dysregulation of angiogenesis is crucial for the pathogenesis of renal and cardiovascular diseases. Endostatin plays a pivotal role in the regulation of angiogenesis. Recent studies have provided evidence that circulating endostatin increases significantly in patients with kidney and heart failure and may also contribute to disease progression.

Key message: In the current review, we summarize the latest findings on preclinical and clinical studies analyzing the impact of endostatin on renal and cardiovascular diseases.

Keywords: Angiogenesis; Cardiovascular diseases; Collagen XVIII; Endostatin; Renal diseases.

Fig. 1

Process of endostatin from generation to function. The figure depicts that collagen XVIII derived from epithelial and endothelial BM includes N-terminal domain, interrupted triple-helical domain and NC1 (a). NC1 is cleaved into 20-kDa endostatin and endostatin-like protein fragments by cathepsins, elastase, and MMPs. Based on previous animal and clinical studies, the levels of endostatin may be systematically upregulated in the kidney, cardiovascular, and some neoplastic diseases, in which circulating endostatin is regarded as a biomarker of occurrence/progression of the disease but mostly downregulated in tissue repair, wound healing, and chronic inflammation, in which locally decreased endostatin may be beneficial for organ/tissue recovery (b). Endostatin binds to integrins, HSPG, VEGFR, and nucleolin to exert different functions on the cell surface, including inhibition of ECs proliferation and migration and induction of apoptosis, which are related to inhibition of angiogenesis. Also, it was reported that endostatin may lead to renal fibrosis in murine models and be a potential prognostic biomarker for the occurrence and progression of kidney diseases. Moreover, in CVD, endostatin may inhibit the progression of AS and MI (c). BM, basement membrane; NC1, C-terminal domain; MMPs, matrix metalloproteinases; HSPG, heparan sulfate proteoglycans; VEGFR, vascular endothelial growth factor receptor; ECs, endothelial cells; CVD, cardiovascular disease; AS, atherosclerosis; MI, myocardial infarction.

Fig. 2

Endostatin expression in renal cortex under physiological conditions (a–c) and in unspecific interstitial nephritis (d). a Glomerular capillaries (1) and mesangium (2) negative, podocytes (3) weakly positive, epithelial cells of the bowman capsule strongly positive (4). b Tubular epithelium strongly positive (distal [5] > proximal [6]), interstitium (7) negative. c Endothelium of larger arteries (8) and capillaries (9) weakly positive, media/adventitia of larger arteries (10) negative. d In interstitial nephritis, plasma cells show strong positivity for endostatin (11). Inflammatory destruction of tubulin likely results in loss of endostatin expression. Immunohistochemistry on paraffin-embedded renal biopsy samples from patients from the University Medical Centre Mannheim, University of Heidelberg, Heidelberg, Germany (Primary antibody: Anti-Endostatin Polyclonal Antibody [bs-0547R]). 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).

Fig. 3

Stage-dependent role of endostatin in CVDs. The figure illustrates the potential role of endostatin in various stages of CVDs, including early plaque formation and growth, early and late stage after MI as well as established HF. CVDs, cardiovascular diseases; MI, myocardial infarction; LV, left ventricular; HF, heart failure.