Childhood nephrotic syndrome (NS) is a debilitating disease which presents with recurrent episodes of selective proteinuria and edema. The kidney pathology in NS reveals extensive podocyte foot process effacement secondary to podocyte cytoskeletal changes as evidenced in vitro by reduced actin stress fibers. The etiology of childhood NS remains largely unknown however, mutations in several podocyte genes can be identified in up to 30% of NS patients. Our recent work revealed that kidney podocytes have features of innate immune cells, and the TLR4 ligand lipopolysaccharide (LPS) induces transient proteinuria through TLR signaling-mediated induction of podocyte B7-1. However, the mechanisms that regulate podocyte TLR signaling and its downstream effects are currently unknown. MicroRNAs (miRNAs) have been identified as important regulators of many biological systems including podocyte homeostasis and podocytopathies as well as of LPS-mediated signaling. Yet, very little is known about the miRNAs that are involved in podocyte homeostasis and/or podocyte TLR signaling. We have recently shown that LPS treatment of mouse podocytes leads to significant changes in expression of 19 miRNAs among 722 miRNAs analyzed. Our further analysis revealed that 6 of these miRNAs had a significant increase in expression after LPS treatment of podocytes, and they are predicted to suppress expression of several podocyte genes that are linked to podocytopathy and to genetic forms of childhood NS. Based on these observations, we hypothesize that miRNAs that are involved in podocyte TLR signaling may lead to proteinuria through their regulatory effects on podocyte genes. Therefore the goals of this proposal are to: 1. Validate podocyte expression profile of 6 miRNAs and their target genes and 2. Determine the physiological importance of these 6 miRNAs in regulation of podocyte target genes and podocythopathy. Childhood NS is the most common glomerular disease and a leading cause of end-stage kidney disease among children. This proposal provides a novel mechanism for the pathogenesis of proteinuria. Validation of our hypothesis will pave the way for new disease markers and individualized therapies that are desperately needed for treatment of this debilitating childhood disease.
Nephrotic syndrome (NS) is the most common glomerular disorder of childhood and is a leading cause of renal failure necessitating kidney transplantation and dialysis among children. Even the mildest form of NS is characteristically a recurrent disorder that increases disease- and treatment-associated complications making it a significant health problem in the pediatric and adult populations. The proposed novel studies provide a unique opportunity to develop a more comprehensive understanding of NS pathogenesis that will result in the development of better and individualized therapies to improve future patient outcomes.