Abstract: FR-OR062

The miRNA-29a to Claudin-1 Pathway Is an important Regulator of Glomerular Albumin Permeation in Diabetic Nephropathy

Session Information

Category: Glomerular

  • 1003 Glomerular: Cell Biology


  • Gong, Yongfeng, Washington University Renal Division, Saint Louis, Missouri, United States
  • Jarad, George, Washington University School of Medicine, St. Louis, Missouri, United States
  • Zhang, Ming-Zhi, Vanderbilt University Medical School, Nashville, Tennessee, United States
  • Harris, Raymond C., Vanderbilt University Medical Center, Nashville, Tennessee, United States
  • Hou, Jianghui, Washington University School of Medicine, St. Louis, Missouri, United States

Diabetic nephropathy (DN) is characterized by alteration in glomerular filtration barrier, which include thickening of the the glomerular basement membrane (GBM), podocyte foot process effacement, reduced slit width and loss of slit diaphragm (SD). The disappearance of the SD is associated with the appearance of the tight junction (TJ) and re-expression of claudin-1 in podocytes, suggesting a previously unknown role for TJ in DN. Hyperglycemia has been shown to suppress the expression of miRNA-29 family in podocytes, which is known to modulate the expression of claudin-1 and extracellular matrix (ECM). These data suggest that miRNA-29a family might play roles in the development of podocyte dysfunction and glomerular phenotype of DN.


We have generated a series of transgenic mouse models to study the role of claudins and microRNAs in DN. Using a nephrin-rtTA mouse model, we have generated podocyte specific overexpression of claudin-1 in tetracycline inducible manner. Using gene targeting approach, we have generated a miRNA-29a knockout mouse model in the kidney.


1. Expression of miRNA-29a is downregulated in the podocytes from the db/db-eNOS mouse model of DN. 2. Knockout of miRNA-29a, the innate regulator of claudin-1 and ECM in podocytes, resulted in progressive proteinuria, accompanied by destabilization of podocyte SD and thickening of the GBM, which are the hallmarks of DN. Mechanistically, such pathologic changes are derived from increased expression of cell junction gene - claudin-1, and in GBM genes - collagen IV alpha3,4,5 and laminin beta2, all of which are direct targets of miRNA-29a. 3. Induction of claudin-1 gene expression in mature podocytes caused albuminuria. Using freeze fracture techniques, we confirmed the cell junction induced by claudin-1 overexpression, which culminate in the transformation of podocyte SD into TJ. Immunolabeling of SD proteins revealed that claudin-1 overexpression destabilized the SD protein complex, with significant reduction and altered localization of nephrin and podocin.


Our data attest to a novel concept that a central signaling pathway from microRNA to claudin-1 may coordinately regulate a wide spectrum of podocyte lesions important to DN. Such a pathway may lead to a new therapeutic aproach to treat DN by manipulating mircoRNA expression.


  • NIDDK Support