Chronic Kidney Disease Is Associated With Increased Cardiac Corin Expression But Decreased Proatrial Natriuretic Peptide Conversion Activity

Figures

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  Figure 1. Mean serum corin levels by chronic kidney disease (CKD) stage and associations of corin levels with left ventricular (LV) mass index. A, Serum corin levels were higher in patients with CKD than in patients without CKD, and, among patients with CKD, a trend of increasing levels with stage progression was observed (P for trend <0.001). B and C, Serum corin levels (log) correlated inversely with LV mass index in participants with preserved renal function (R=−0.355, P=0.001) but not in the patients with CKD. Non‐CKD, n=184; CKD stage 3, n=233; CKD stage 4, n=49; CKD stage 5, n=775. *P<0.05, **P<0.001 vs non‐CKD.

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  Figure 2. Chronic kidney disease (CKD) mice develop cardiac hypertrophy and fibrosis. A, Representative cross‐sections of the left ventricle in CKD and control mice. B, Heart weight ratios by group. C and D, Size analysis of wheat germ agglutinin (WGA)–stained cardiomyocytes revealed that CKD hearts had larger cardiomyocytes than controls. E and F, Analyses of Masson trichrome–stained left ventricles showed that CKD mice showed greater fibrosis development than did controls. G and H, The expression of hypertrophy (Myh7b) and fibrosis (Col1a1) associated genes were upregulated in CKD mice. *P<0.05, **P<0.001 between groups. H&E indicates hematoxylin and eosin.

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  Figure 3. Chronic kidney disease (CKD) model mice exhibit elevated serum corin levels and cardiac corin expression. A, Serum corin levels before, 4 weeks after, and 8 weeks after 5/6 nephrectomy or sham surgery. B, Relative mRNA expression of the corin gene. C, Western blot for corin protein quantitation in cardiac tissues. D, Corin protein expression levels in sham control mouse and CKD mouse heart tissues 8 weeks postsurgery. E and F, Immunohistochemistry (IHC) staining for corin shows enhanced cytoplasmic corin labeling in CKD mouse heart tissues 8 weeks postsurgery. G and H, Proatrial natriuretic peptide conversion assay and associated calculated conversion ratio data (8 weeks postsurgery). *P<0.05, **P<0.001 between groups. ANP indicates atrial natriuretic peptide.

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  Figure 4. Elevated serum in chronic kidney disease (CKD) mice and a strong association of serum indoxyl sulfate (IS) with serum corin levels. A, Serum IS levels. B, Positive correlation between serum corin and serum IS levels. *P<0.05, **P<0.001 between groups.

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  Figure 5. Indoxyl sulfate (IS) stimulates hypertrophy, stimulates fibrosis, and modulates corin expression in H9c2 cardiomyoblasts. A and B, IS upregulates Myh7b and Col1a1 in cultured H9C2 cardiomyoblasts. C through E, Stimulatory effect of IS on relative corin mRNA (C) and protein expression (D and E). F, In contrast with our corin protein expression data in (E), corin activity was elevated at a low IS concentration but suppressed at high IS concentrations. *P<0.05, **P<0.001 vs control; all experiments were performed in triplicate.

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  Figure 6. PCSK6 (proprotein convertase subtilisin/kexin type 6) expression is suppressed in H9c2 cardiomyoblasts and chronic kidney disease (CKD) hearts treated with indoxyl sulfate (IS). A and B, In H9c2 cardiomyoblasts, both PCSK6 mRNA (A) and protein (B) levels decreased after IS treatment. C and D, Cardiac expression of PCSK6 mRNA (C) and protein (D) was suppressed in CKD mice. *P<0.05, **P<0.001 vs control; all experiments were performed in triplicate.