MicroRNA in Diabetic and TGFbeta-Related Renal Glomerulopathy.

[摘要] Chronic kidney disease (CKD) decreases quality of life, increases mortality, and has limited treatment options. Glomerular injury is an early stage of diabetic nephropathy (DN), which is a leading cause of CKD, and is characterized by mesangial cell proliferation and hypertrophy, loss of podocytes, and increased extracellular matrix (ECM) deposition. Critical aspects of these cellular events are mediated by activation of the Transforming Growth Factor-beta (TGFβ) signaling cascade. MicroRNAs (miRNAs) regulate gene expression in a post-transcriptional level and have been implicated as important regulatory elements in the TGFβ signaling cascade. To determine the role of miRNAs in DN, we examined miRNA expression in micro-dissected glomeruli from kidney biopsies of patients with clinically early DN and correlated the expression levels with clinical manifestations.We determined that miR-21 exhibits high expression in renal glomeruli and significant correlation with urine albumin-to-creatinine-ratio (ACR) of patients. miR-21 is a known regulator of TGFβ signaling and its level is positively associated with severity of renal phenotype in TGFβ transgenic mice. We further found that loss of miR-21 in TGFβ transgenic mice resulted in accelerated podocyte apoptosis and glomerulosclerosis. A similar phenotype was detected in streptozotocin-induced diabetic mice. In cultured glomerular cells, loss or inhibition of miR-21 led to increased apoptosis of podocytes and increased proliferation of primary mesangial cells. Further studies showed that miR-21 represses multiple pro-apoptotic pathways, including TGFβ/Smad7, P53, and PDCD4, cell cycle-related genes such as Cdk6 and Cdc25a, and ECM-related genes. These results suggest that miR-21 ameliorates glomerular injury through repression of multiple injury-mediating signaling pathways. To further elucidate a miRNA-mediated network mediating DN progression, we examined mRNA expression in the same glomerular samples. We identified ACR-associated genes that are predicted targets of ACR-associated miRNAs and experimentally validated the sequence-dependent repression of candidate target genes of miR-200a. This led to the discovery of EXOC7 as a sequence-dependent target of miR-200a.In summary, correlating miRNA expression with specific clinical outcomes identified novel mechanisms regulating DN, including a protective role for miR-21 in glomerular injury. Furthermore, the approach, which links disease-associated miRNAs and mRNAs by target prediction, appears to facilitate identification of context-relevant miRNA-mRNA interactions.

[发布机构] University of Michigan

[效力级别] MicroRNA

[关键词] Diabetic Nephropathy;MicroRNA;Molecular;Cellular and Developmental Biology;Science;Cellular & Molecular Biology