Soluble urokinase plasminogen activator receptor (suPAR) independently
predicts chronic kidney disease (CKD) incidence and progression. Apolipoprotein
L1 (APOL1) gene variants G1 and G2, but not the reference allele (G0), are
associated with an increased risk of CKD in individuals of recent African
ancestry. Here we show in two large, unrelated cohorts that decline in kidney
function associated with APOL1 risk variants was dependent on
plasma suPAR levels: APOL1-related risk was attenuated in
patients with lower suPAR, and strengthened in those with higher suPAR levels.
Mechanistically, surface plasmon resonance studies identified high-affinity
interactions between suPAR, APOL1 and αvβ3
integrin, whereby APOL1 protein variants G1 and G2 exhibited higher affinity for
suPAR-activated avb3 integrin than APOL1 G0. APOL1 G1 or G2 augments
αvβ3 integrin activation and causes
proteinuria in mice in a suPAR-dependent manner. The synergy of circulating
factor suPAR and APOL1 G1 or G2 on αvβ3
integrin activation is a mechanism for CKD.
Background: CYP2D6-mediated drug metabolism is enhanced during pregnancy, but the underlying mechanisms remain unknown. Results: In CYP2D6-humanized mice, CYP2D6 induction during pregnancy was linked to decreased expression of SHP, a repressor of CYP2D6 expression. Conclusion: Decreased SHP expression may account for CYP2D6 induction during pregnancy. Significance: This may provide a mechanistic basis in designing optimal dosage regimens in pregnant women.
These results indicate that the SRI is highly reliable and valid, and that it can be utilized as an effective measure of stress for research in stress-related fields. The depressive disorder group showed more prominent stress responses than the anxiety and psychosomatic disorder groups.
Epigenetic modification of gene expression plays an important role in the development of human cancers. The inactivation of SPARC through CpG island methylation was studied in colon cancers using oligonucleotide microarray analysis and methylation specific PCR (MSP). Gene expression of 7 colon cancer cell lines was evaluated before and after treatment with the demethylating agent 5-aza-2 0 -deoxycytidine (5Aza-dC) by oligonucleotide microarray analysis. Expression of SPARC was further examined in colon cancer cell lines and primary colorectal cancers, and the methylation status of the SPARC promoter was determined by MSP. SPARC expression was undetectable in 5 of 7 (71%) colorectal cancer cell lines. Induction of SPARC was demonstrated after treatment with the demethylating agent 5Aza-dC in 5 of the 7 cell lines. We examined the methylation status of the CpG island of SPARC in 7 colon cancer cell lines and in 20 test set of colon cancer tissues. MSP demonstrated hypermethylation of the CpG island of SPARC in 6 of 7 cell lines and in all 20 primary colon cancers, when compared with only 3 of 20 normal colon mucosa. Immunohistochemical analysis showed that SPARC expression was downregulated or absent in 17 of 20 colon cancers. A survival analysis of 292 validation set of colorectal carcinoma patients revealed a poorer prognosis for patients lacking SPARC expression than for patients with normal SPARC expression (56.79% vs. 75.83% 5-year survival rate, p 5 0.0014). The results indicate that epigenetic gene silencing of SPARC is frequent in colon cancers, and that inactivation of SPARC is related to rapid progression of colon cancers. ' 2007 Wiley-Liss, Inc.
Edited by Xiao-Fan WangPodocyte injury is an early event in diabetic kidney disease and is a hallmark of glomerulopathy. MicroRNA-146a (miR146a) is highly expressed in many cell types under homeostatic conditions, and plays an important anti-inflammatory role in myeloid cells. However, its role in podocytes is unclear. Here, we show that miR-146a expression levels decrease in the glomeruli of patients with type 2 diabetes (T2D), which correlates with increased albuminuria and glomerular damage. miR-146a levels are also significantly reduced in the glomeruli of albuminuric BTBR ob/ob mice, indicating its significant role in maintaining podocyte health. miR-146a-deficient mice (miR-146a
Conflict of interest:JR and SS are inventors on pending and issued patents related to antiproteinuric therapies. They stand to gain royalties from present and future commercialization. They also are cofounders and advisors to TRISAQ, a biotechnology company. CW has a pending patent on suPAR in diabetes. He stands to gain royalties from future commercialization products concerning this application (see Supplemental Data for complete information).
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