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Vitronectin accumulates in the interstitium but minimally impacts fibrogenesis in experimental chronic kidney disease.

ABSTRACT: Vitronectin (Vtn) is a glycoprotein found in normal serum and pathological extracellular matrix. Given its known interactions with plasminogen activator inhibitor-1 (PAI-1) and Vtn cellular receptors, especially ?v?3 integrin and the urokinase receptor (uPAR), this study was designed to investigate its role in renal fibrogenesis in the mouse model of unilateral ureteral obstruction (UUO). Kidney Vtn mRNA levels were increased ×1.8-5.1 and Vtn protein levels ×1.9-3 on days 7, 14, and 21 after UUO compared with sham kidney levels. Groups of age-matched C57BL/6 wild-type (Vtn+/+) and Vtn-/- mice (n = 10-11/group) were killed 7, 14, or 21 days after UUO. Absence of Vtn resulted in the following significant differences, but only on day 14: fewer ?SMA+ interstitial myofibroblasts (×0.53), lower procollagen III mRNA levels (×0.41), lower PAI-1 protein (×0.23), higher uPA activity (×1.1), and lower ?v protein (×0.32). The number of CD68+ macrophages did not differ between the genotypes. Despite these transient differences on day 14, the absence of Vtn had no effect on fibrosis severity based on both picrosirius red-positive interstitial area and total kidney collagen measured by the hydroxyproline assay. These findings suggest that despite significant interstitial Vtn deposition in the UUO model of chronic kidney disease, its fibrogenic role is either nonessential or redundant. These data are remarkable given Vtn's strong affinity for the potent fibrogenic molecule PAI-1.

SUBMITTER: Lopez-Guisa JM

PROVIDER: S-EPMC3094052 | biostudies-literature | 2011 May

REPOSITORIES: biostudies-literature

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Vitronectin accumulates in the interstitium but minimally impacts fibrogenesis in experimental chronic kidney disease.

López-Guisa Jesús M JM Rassa Allen C AC Cai Xiaohe X Collins Sarah J SJ Eddy Allison A AA

American journal of physiology. Renal physiology 20110126 5

Vitronectin (Vtn) is a glycoprotein found in normal serum and pathological extracellular matrix. Given its known interactions with plasminogen activator inhibitor-1 (PAI-1) and Vtn cellular receptors, especially αvβ3 integrin and the urokinase receptor (uPAR), this study was designed to investigate its role in renal fibrogenesis in the mouse model of unilateral ureteral obstruction (UUO). Kidney Vtn mRNA levels were increased ×1.8-5.1 and Vtn protein levels ×1.9-3 on days 7, 14, and 21 after UUO ...[more]

PMID: 21270094

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Project description:BackgroundChronic Kidney Disease (CKD) is a leading public health problem, with substantial burden and economic implications for healthcare systems, mainly due to renal replacement treatment (RRT) for end-stage kidney disease (ESKD). The aim of this study is to develop a multistate predictive model to estimate the future burden of CKD in Chile, given the high and rising RRT rates, population ageing, and prevalence of comorbidities contributing to CKD.MethodsA dynamic stock and flow model was developed to simulate CKD progression in the Chilean population aged 40 years and older, up to the year 2041, adopting the perspective of the Chilean public healthcare system. The model included six states replicating progression of CKD, which was assumed in 1-year cycles and was categorised as slow, medium or fast progression, based on the underlying conditions. We simulated two different treatment scenarios. Only direct costs of treatment were included, and a 3% per year discount rate was applied after the first year. We calibrated the model based on international evidence; the exploration of uncertainty (95% credibility intervals) was undertaken with probabilistic sensitivity analysis.ResultsBy the year 2041, there is an expected increase in cases of CKD stages 3a to ESKD, ceteris paribus, from 442,265 (95% UI 441,808-442,722) in 2021 to 735,513 (734,455-736,570) individuals. Direct costs of CKD stages 3a to ESKD would rise from 322.4M GBP (321.7-323.1) in 2021 to 1,038.6M GBP (1,035.5-1,041.8) in 2041. A reduction in the progression rates of the disease by the inclusion of SGLT2 inhibitors and pre-dialysis treatment would decrease the number of individuals worsening to stages 5 and ESKD, thus reducing the total costs of CKD by 214.6M GBP in 2041 to 824.0M GBP (822.7-825.3).ConclusionsThis model can be a useful tool for healthcare planning, with development of preventive or treatment plans to reduce and delay the progression of the disease and thus the anticipated increase in the healthcare costs of CKD.

Dataset Information

Vitronectin accumulates in the interstitium but minimally impacts fibrogenesis in experimental chronic kidney disease.

Publications

Vitronectin accumulates in the interstitium but minimally impacts fibrogenesis in experimental chronic kidney disease.

Similar Datasets

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