Abstract
The aims of the present study were to elucidate a possible mechanism of kidney crystal formation by using a metabolic syndrome (MetS) mouse model and to assess the effectiveness of adiponectin treatment for the prevention of kidney crystals. Further, we performed genome-wide expression analyses for investigating novel genetic environmental changes. Wild-type (+/+) mice showed no kidney crystal formation, whereas ob/ob mice showed crystal depositions in their renal tubules. However, this deposition was remarkably reduced by adiponectin. Expression analysis of genes associated with MetS-related kidney crystal formation identified 259 genes that were >2.0-fold up-regulated and 243 genes that were <0.5-fold down-regulated. Gene Ontology (GO) analyses revealed that the up-regulated genes belonged to the categories of immunoreaction, inflammation, and adhesion molecules and that the down-regulated genes belonged to the categories of oxidative stress and lipid metabolism. Expression analysis of adiponectin-induced genes related to crystal prevention revealed that the numbers of up- and down-regulated genes were 154 and 190, respectively. GO analyses indicated that the up-regulated genes belonged to the categories of cellular and mitochondrial repair, whereas the down-regulated genes belonged to the categories of immune and inflammatory reactions and apoptosis. The results of this study provide compelling evidence that the mechanism of kidney crystal formation in the MetS environment involves the progression of an inflammation and immunoresponse, including oxidative stress and adhesion reactions in renal tissues. This is the first report to prove the preventive effect of adiponectin treatment for kidney crystal formation by renoprotective activities and inhibition of inflammation and apoptosis.
Highlights
The worldwide prevalence of kidney stone formation increased in the last quarter of the 20th century [1]
We reported renal proximal tubular cell injury and oxidative stress caused by a mitochondrial disorder in the early phase of kidney crystal formation [9]
We investigated the following 3 points to elucidate the mechanism of kidney crystal formation under the metabolic syndrome (MetS) environment as well as the efficacy of exogenous APN treatment as an MetS prophylactic agent for kidney crystal prevention: (i) mineral environmental changes in blood and urine, (ii) expression changes and renal distribution of previously reported kidney crystal-related genes and endogenous APN, and (iii) novel genetic environmental changes in the kidney by using a genome-wide analysis
Summary
The worldwide prevalence of kidney stone formation increased in the last quarter of the 20th century [1]. We detected osteopontin (OPN) as a stone matrix protein [6] and reported an increase in renal OPN expression by using a crystal formation animal model [7]. We reported renal proximal tubular cell injury and oxidative stress caused by a mitochondrial disorder in the early phase of kidney crystal formation [9]. This mechanism of kidney crystal formation is very similar to that of atherosclerosis and was the basis of our hypothesis that kidney crystal formation is a metabolic syndrome (MetS)-related disease
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