Kallistatin: A Novel Biomarker for Hypertension, Organ Injury and Cancer

Special Article – Molecular Biomarkers

Austin Biomark Diagn. 2015; 2(2): 1019.

Kallistatin: A Novel Biomarker for Hypertension, Organ Injury and Cancer

Julie Chao*, Grant Bledsoe and Lee Chao

Department of Biochemistry and Molecular Biology, Medical University of South Carolina, USA

*Corresponding author: Julie Chao, Department of Biochemistry and Molecular Biology, Medical University of South Carolina, 173 Ashley Ave., Charleston, South Carolina, USA

Received: June 15, 2015; Accepted: September 01, 2015; Published: September 07, 2015


Kallistatin has pleiotropic effects in vasodilation and inhibition of inflammation, angiogenesis, oxidative stress, fibrosis, and cancer progression. Kallistatin administration by gene or protein delivery is observed to offer protection against a large number of pathological conditions in animal models, such as hypertension, cardiovascular and organ damage, arthritis, sepsis, influenza virus infection, tumor growth and metastasis. However, injection of a neutralizing Kallistatin antibody into hypertensive rats aggravates cardiovascular and renal injury in association with increased inflammation, oxidative stress and tissue remodeling. Thus, animal studies show that kallistatin treatment exerts beneficial effects against hypertension, organ damage and cancer development. Moreover, serum kallistatin levels are markedly reduced in several animal models of hypertension and cardiac, cerebral and renal injury. Importantly, kallistatin levels in circulation, body fluids or tissues are significantly lower in patients with liver disease, septic syndrome, diabetic retinopathy, severe pneumonia, inflammatory bowel disease, and cancer of the colon and prostate. Furthermore, reduced plasma kallistatin levels are associated with adiposity and metabolic risk in apparently healthy African American youths. The focus of this review is to highlight circulating kallistatin as a potential new biomarker for human diseases.

Keywords: Kallistatin; Hypertension; Inflammation; Vascular injury; Organ damage; Infection; Sepsis; Cancer


eNOS: endothelial Nitric Oxide Synthase; EPC: Endothelial Progenitor Cell; HMGB1: High Mobility Group Box-1; I/R: Ischemia/Reperfusion; KBP: Kallikrein-Binding Protein; LPS: Lipopolysaccharide; MI: Myocardial Infarction; NO: Nitric Oxide; ROS: Reactive Oxygen Species; SHR: Spontaneously Hypertensive Rat; SOCS3: Suppressor of Cytokine Signaling 3; SPTBN1: β II-Spectrin; STZ: Streptozotocin; TGF-β: Transforming Growth Factor-β; TLR4: Toll-Like Receptor 4; TNF-a: Tumor Necrosis Factor-a; VEGF: Vascular Endothelial Growth Factor


Kallistatin is an endogenous protein that was first discovered in human plasma as a tissue Kallikrein-Binding Protein (KBP) [1]. Tissue kallikrein is a serine proteinase that releases vasodilating kinin peptides from kininogen substrate [2]. The tissue kallikrein-kinin system is involved in mediating beneficial effects in hypertension as well as cardiac, cerebral and renal injury [3]. KBP was later identified as a serine proteinase inhibitor (serpin) because of its ability to inhibit tissue kallikrein activity, and was subsequently named “kallistatin” [4-9]. Kallistatin is mainly expressed in the liver, but is also present in the heart, kidney and blood vessel [9-11]. Kallistatin protein contains two structural elements: an active site and a heparin-binding domain [12-14]. The active site of kallistatin is crucial for complex formation with tissue kallikrein, and thus tissue kallikrein inhibition [6]. Kallistatin sheparin-binding domain, however, is essential for antagonizing signaling pathways mediated by Vascular Endothelial Growth Factor (VEGF), Tumor Necrosis Factor (TNF)-a, High Mobility Group Box-1 (HMGB1), and Transforming Growth Factor (TGF)-β [15-18]. Through its structural elements, kallistatin is able to modulate a wide spectrum of biological activities, such as blood pressure, angiogenesis, inflammation, apoptosis, fibrosis, and cancer.

Reduced kallistatin levels are associated with hypertension

Kallistatin is expressed in tissues relevant to cardiovascular function, and has consequently been shown to have vasodilating properties [19]. Spontaneously Hypertensive Rats (SHR) display markedly reduced circulating kallistatin levels compared to normotensive rats, indicating that kallistatin may be involved in maintaining normal blood pressure [5,20]. In addition to SHR, salt- and surgically-induced hypertensive rats exhibit decreased serum kallistatin levels, as measured by specific Enzyme-Linked Immunosorbent Assay (ELISA) [21] (Figure 1). Kallistatin has been demonstrated to stimulate vasodilation, as an intravenous injection of purified kallistatin induced a rapid and transient reduction of blood pressure in both normotensive and hypertensive rats [19]. Vasorelaxation in isolated rataortic rings was also observed upon kallistatin administration [19]. Neither the blood pressure-lowering effect nor the vasorelaxation ability of kallistatin was abolished by icatibant (Hoe140, a kinin B2receptor antagonist), indicating that kallistatin-mediated vasodilation is unrelated to the tissue kallikreinkinin system [19]. Furthermore, over expression of rat kallistatin in transgenic mice resulted in significantly lower blood pressure as compared to control mice [22]. Likewise, gene delivery of human kallistatin caused a protracted blood pressure reduction in SHR [23]. These studies demonstrate that kallistatin is a novel vasodilating agent; and that circulating kallistatin levels are associated with the development of hypertension.