Novel markers of left ventricular hypertrophy in uremia

Abstract

Aims: Left ventricular hypertrophy (LVH) is the most frequent cardiac complication in chronic renal disease. Previous studies implicate elevated serum phosphorus as a risk factor for LVH.

Methods: We treated 5/6 nephrectomized rats with enalapril or enalapril + sevelamer carbonate for 4 months to determine if sevelamer carbonate had an additional beneficial effect on the development of LVH and uremia-induced left ventricle (LV) remodeling.

Results: Uremia increased LV weight and cardiomyocyte size. Enalapril and enalapril + sevelamer blunted the increase in left ventricular weight. Only enalapril + sevelamer diminished the increase in cardiomyocyte size. Uremia increased cyclin D2 and PCNA and decreased p27 protein expression in the heart. Enalapril + sevelamer diminished the decrease in p27 expression caused by uremia. Uremia increased Ki67-positive and phosphohistone H(3)-positive interstitial cells. This was not seen in cardiomyocytes. Multivariable regression analysis showed that increased phosphorus was an independent risk factor for both increased LV weight and cardiomyocyte size.

Conclusions: These data suggest left ventricular remodeling consists of cardiomyocyte hypertrophy and interstitial cell proliferation, but not cardiomyocyte proliferation. p27 and cyclin D2 may play important roles in the development of LVH. In addition, phosphorus can be an independent risk factor for the development of LVH.

Fig. 1.

Effect of enalapril and the combination of both enalapril and sevelamer carbonate on (a) left ventricular weight (LV) and (b) cardiomyocyte size. a^a p < 0.001 vs. NC, ^b p < 0.01 vs. UE, ^c p < 0.01 vs. UES, ^d p < 0.001 vs. NC, and ^e p < 0.01 vs. NC. b^a p < 0.01 vs. NC, ^b p < 0.05 vs. UES, and ^c p < 0.05 vs. NC. c Masson trichrome staining of cardiomyocytes in NC, UC, UE and UES rat hearts. Results were expressed as mean ± SEM. p values were obtained by ANOVA followed by Bonferroni post tests. 254 × 190 mm (96 × 96 dpi).

Fig. 2.

Western blot analysis showing the effect of enalapril and the combination of both enalapril and sevelamer carbonate on the expression of cyclin D2 in the LV. a Representative Western blot of cyclin D2 and GAPDH (glyceraldehyde 3-phosphate dehydrogenase). b Quantification of several analyses. Cyclin D2 was normalized to GAPDH. Results were expressed as mean ± SEM. p values were obtained by ANOVA followed by Bonferroni post test. ^a p < 0.01 vs. NC. 254 × 190 mm (96 × 96 dpi).

Fig. 3.

Western blot analysis showing the effect of enalapril and the combination of both enalapril and sevelamer carbonate on the expression of p27 in the LV. a Representative Western blot of p27 and GAPDH (glyceraldehyde 3-phosphate dehydrogenase). b Quantification of several analyses. p27 as normalized to GAPDH. Results were expressed as mean ± SEM. p values were obtained by ANOVA followed by Bonferroni post test. ^a p < 0.01 vs. NC and ^b p < 0.05 vs. UES. 254 × 190 mm (96 × 96 dpi).

Fig. 4.

Western blot analysis showing the effect of enalapril and the combination of both enalapril and sevelamer carbonate on the expression of PCNA in the LV. a Representative Western blot of PCNA and GAPDH (glyceraldehyde 3-phosphate dehydrogenase). b Quantification of several analyses. PCNA was normalized to GAPDH. Results were expressed as mean ± SEM. p values were obtained by ANOVA followed by Bonferroni post tests. ^a p < 0.01 vs. NC and ^b p < 0.05 vs. NC. 254 × 190 mm (96 × 96 dpi).

Fig. 5.

Effect of enalapril and the combination of both enalapril and sevelamer carbonate on Ki67 expression in the LV. a Quantification of Ki67-positive interstitial cells. ^a p < 0.01 vs. NC and ^b p < 0.05 vs. NC. b Immunohistochemical staining for Ki67 (brown in the online version) in the LVs of NC and UC rats. 254 × 190 mm (96 × 96 dpi).

Fig. 6.

Effect of enalapril and the combination of both enalapril and sevelamer carbonate on PHH₃ expression in the LV. a Quantification of PHH₃-positive interstitial cells. ^a p < 0.05 vs. NC. b Immunohistochemical staining for PHH₃ (brown in the online version) in NC and UC LVs. 254 × 190 mm (96 × 96 dpi).