Elastin Degradation and Vascular Smooth Muscle Cell Phenotype Change Precede Cell Loss and Arterial Medial Calcification in a Uremic Mouse Model of Chronic Kidney Disease

• Published in: The American journal of pathology Vol. 178; no. 2; pp. 764 - 773
• Main Authors: Pai, Ashwini, Leaf, Elizabeth M, El-Abbadi, Mohga, Giachelli, Cecilia M
• Format: Journal Article
• Language: English
• Published: Bethesda, MD Elsevier Inc 01.02.2011; American Society for Investigative Pathology
• Subjects: Animals; Biological and medical sciences; Calcinosis - blood; Calcinosis - complications; Cell Death - drug effects; Diet; Disease Models, Animal; Disease Progression; Elastin - metabolism; Enzyme Activation - drug effects; Immunohistochemistry; Investigative techniques, diagnostic techniques (general aspects); Kidney Failure, Chronic - blood; Kidney Failure, Chronic - complications; Kidney Failure, Chronic - enzymology; Kidney Failure, Chronic - pathology; Kidneys; Matrix Metalloproteinases - metabolism; Medical sciences; Mice; Muscle, Smooth, Vascular - pathology; Myocytes, Smooth Muscle - drug effects; Myocytes, Smooth Muscle - pathology; Nephrology. Urinary tract diseases; Nephropathies. Renovascular diseases. Renal failure; Pathology; Pathology. Cytology. Biochemistry. Spectrometry. Miscellaneous investigative techniques; Phenotype; Phosphates - administration & dosage; Phosphates - pharmacology; Regular; Renal failure; Time Factors; Tunica Media - drug effects; Tunica Media - pathology; Uremia - blood; Uremia - complications; Uremia - enzymology; Urinary system involvement in other diseases. Miscellaneous; Kidney disease; Animal model; Urinary system disease; Elastin; Rodentia; Smooth muscle; Chronic kidney disease; Artery; Myocyte; Degradation; Vertebrata; Anatomic pathology; Phenotype; Mammalia; Mouse; Cell death; Blood vessel; Renal failure; Calcification; Circulatory system
• ISSN: 0002-9440; 1525-2191
• DOI: 10.1016/j.ajpath.2010.10.006

Arterial medial calcification (AMC), a hallmark of vascular disease in uremic patients, is highly correlated with serum phosphate levels and cardiovascular mortality. To determine the mechanisms of AMC, mice were made uremic by partial right-side renal ablation (week 0), followed by left-side nephrectomy at week 2. At 3 weeks, mice were switched to a high-phosphate diet, and various parameters of disease progression were examined over time. Serum phosphate, calcium, and fibroblast growth factor 23 (FGF-23) were up-regulated as early as week 4. Whereas serum phosphate and calcium levels declined to normal by 10 weeks, FGF-23 levels remained elevated through 16 weeks, consistent with an increased phosphate load. Elastin turnover and vascular smooth muscle cell (VSMC) phenotype change were early events, detected by week 4 and before AMC. Both AMC and VSMC loss were significantly elevated by week 8. Matrix metalloprotease 2 (MMP-2) and cathepsin S were present at baseline and were significantly elevated at weeks 8 and 12. In contrast, MMP-9 was not up-regulated until week 12. These findings over time suggest that VSMC phenotype change and VSMC loss (early phosphate-dependent events) may be necessary and sufficient to promote AMC in uremic mice fed a high-phosphate diet, whereas elastin degradation might be necessary but is not sufficient to induce AMC (because elastin degradation occurred also in uremic mice on a normal-phosphate diet, but they did not develop AMC).