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Depletion of Endogenous Kallistatin Exacerbates Renal and Cardiovascular Oxidative Stress, Inflammation, and Organ Remodeling

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Depletion of Endogenous Kallistatin Exacerbates Renal and Cardiovascular Oxidative Stress, Inflammation, and Organ Remodeling

Yuying Liu et al. Am J Physiol Renal Physiol.

Abstract

Kallistatin (KS) levels are reduced in the kidney and blood vessels under oxidative stress conditions. To determine the function of endogenous KS in the renal and cardiovascular systems, KS levels were depleted by daily injection of anti-rat KS antibody into DOCA-salt hypertensive rats for 10 days. Administration of anti-KS antibody resulted in reduced KS levels in the circulation but increased levels of serum thiobarbituric acid reactive substances (an indicator of lipid peroxidation) as well as superoxide formation in the aorta. Moreover, anti-KS antibody injection resulted in increased NADH oxidase activity and superoxide production but decreased nitric oxide levels in the kidney and heart. Endogenous KS blockade aggravated renal dysfunction, damage, hypertrophy, inflammation, and fibrosis as evidenced by decreased creatinine clearance and increased serum creatinine, blood urea nitrogen and urinary protein levels, tubular dilation, protein cast formation, glomerulosclerosis, glomerular enlargement, inflammatory cell accumulation, and collagen deposition. In addition, rats receiving anti-KS antibody had enhanced cardiac injury as indicated by cardiomyocyte hypertrophy, inflammation, myofibroblast accumulation, and fibrosis. Renal and cardiac injury caused by endogenous KS depletion was accompanied by increases in the expression of the proinflammatory genes tumor necrosis factor-α and intercellular adhesion molecule-1 and the profibrotic genes collagen I and III, transforming growth factor-β, and tissue inhibitor of metalloproteinase-1. Taken together, these results implicate an important role for endogenous KS in protection against salt-induced renal and cardiovascular injury in rats by suppressing oxidative stress, inflammation, hypertrophy, and fibrosis.

Figures

Fig. 1.
Fig. 1.
Blockade of endogenous kallistatin by anti-kallistatin (KS) antibody promotes oxidative stress in the aorta and circulation of DOCA-salt rats. A: superoxide detection by in situ oxidation of the fluorescent dye hydroethidine (HE). Red fluorescence indicates oxidation of HE to ethidium; green fluorescence represents aortic elastin fibers. Original magnification = ×200. B: measurement of superoxide in aortic ring segments by lucigenin-enhanced chemiluminescence; rlu, relative light units. C: serum concentration of thiobarbituric acid reactive substances (TBARS), an index of lipid peroxidation. Data are expressed as means ± SE. *P < 0.05 and ‡P < 0.01 vs. sham; †P < 0.05 and §P < 0.01 vs. DOCA/IgG.
Fig. 2.
Fig. 2.
Blockade of endogenous kallistatin by anti-KS antibody promotes oxidative stress in the kidney and heart of DOCA-salt rats. Renal superoxide formation (A), NADH oxidase activity (B), and nitrate/nitrite (NOx) production (C). Cardiac superoxide formation (D), NADH oxidase activity (E), and NOx production (F). Data are expressed as means ± SE. *P < 0.05 and ‡P < 0.01 vs. sham; †P < 0.05 and §P < 0.01 vs. DOCA/IgG.
Fig. 3.
Fig. 3.
Blockade of endogenous kallistatin by anti-KS antibody worsens renal injury and inflammation in DOCA-salt rats. A: representative images of periodic acid-Schiff (PAS) and silver histochemical staining, and ED-1 immunohistochemical staining in the renal cortex. Original magnification is ×200. B: semiquantitative glomerular sclerotic score. C: semiquantitative glomerular hypertrophy score. D: quantification of monocytes/macrophages in the interstitium and within glomeruli. Data are expressed as means ± SE. ‡P < 0.01 vs. sham; §P < 0.01 vs. DOCA/IgG.
Fig. 4.
Fig. 4.
Blockade of endogenous kallistatin by anti-KS antibody exacerbates renal fibrosis in DOCA-salt rats. A: representative images of Sirius red histochemical staining and α-smooth muscle actin (α-SMA) immunohistochemical staining in the renal cortex. Original magnification = ×200. B: quantification of collagen fraction volume. C: quantification of myofibroblasts. Data are expressed as means ± SE. *P < 0.05 and ‡P < 0.01 vs. sham; §P < 0.01 vs. DOCA/IgG.
Fig. 5.
Fig. 5.
Blockade of endogenous kallistatin by anti-KS antibody worsens cardiac injury and inflammation in DOCA-salt rats. A: representative images of hematoxylin and eosin (H&E) and silver histochemical staining, and ED-1 immunohistochemical staining in the heart. Original magnification = ×200. B: quantification of cardiomyocyte size. C: expression levels of the hypertrophic marker ANP as determined by real-time PCR. D: quantification of monocytes/macrophages in the heart. Data are expressed as means ± SE. *P < 0.05 and ‡P < 0.01 vs. sham; †P < 0.05 and §P < 0.01 vs. DOCA/IgG.
Fig. 6.
Fig. 6.
Blockade of endogenous kallistatin by anti-KS antibody exacerbates cardiac fibrosis in DOCA-salt rats. A: representative images of Sirius red histochemical staining and α-SMA immunohistochemical staining. Original magnification = ×200. B: quantification of collagen fraction volume. C: quantification of myofibroblasts. Data are expressed as means ± SE. *P < 0.05 and ‡P < 0.01 vs. sham; †P < 0.05 and §P < 0.01 vs. DOCA/IgG.

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