title: 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.
abstract: 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).
authors.affiliation: Department of Bioengineering, University of Washington, Seattle, Washington, USA.
authors.forename: Ashwini
authors.initials: A
authors.lastname: Pai
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Leaf
authors.forename: Mohga
authors.initials: M
authors.lastname: El-Abbadi
authors.forename: Cecilia M
authors.initials: CM
authors.lastname: Giachelli
mesh_terms: D000818:Animals; D002114:Calcinosis / Q000097:blood / Q000150:complications*; D016923:Cell Death / Q000187:drug effects; D004032:Diet; D004195:Disease Models, Animal; D018450:Disease Progression; D004549:Elastin / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D000089703:Fibroblast Growth Factor-23; D007150:Immunohistochemistry; D007676:Kidney Failure, Chronic / Q000097:blood / Q000150:complications* / Q000201:enzymology / Q000473:pathology; D020782:Matrix Metalloproteinases / Q000378:metabolism; D051379:Mice; D009131:Muscle, Smooth, Vascular / Q000473:pathology*; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000473:pathology*; D010641:Phenotype; D010710:Phosphates / Q000008:administration & dosage / Q000494:pharmacology; D013997:Time Factors; D017540:Tunica Media / Q000187:drug effects / Q000473:pathology*; D014511:Uremia / Q000097:blood / Q000150:complications* / Q000201:enzymology
chemical_list: C000717428:Fgf23 protein, mouse; D010710:Phosphates; D000089703:Fibroblast Growth Factor-23; D004549:Elastin; D020782:Matrix Metalloproteinases