Podocyte-Specific Deletion of Dicer Alters Cytoskeletal Dynamics and Causes Glomerular Disease

Abstract

MicroRNAs (miRNAs) regulate gene expression by binding the 3Ј untranslated region of mRNAs. To define their role in glomerular function, miRNA biogenesis was disrupted in mouse podocytes using a conditional Dicer allele. Mutant mice developed proteinuria by 3 wk after birth and progressed rapidly to end-stage kidney disease. Podocyte pathology included effacement, vacuolization, and hypertrophy with crescent formation. Despite normal expression of WT1, podocytes underwent dedifferentiation, exemplified by cytoskeletal disruption with early transcriptional downregulation of synaptopodin. These abnormalities differed from Cd2ap Ϫ/Ϫ mice, indicating they were not a general consequence of glomerular disease. Glomerular labeling of ezrin, moesin, and gelsolin was altered at 3 wk, but expression of nestin and ␣-actinin was unchanged. Abnormal cell proliferation or apoptosis was not responsible for the glomerular injury. Mutant podocytes were incapable of synthesizing mature miRNA, as revealed by their loss of miR-30a. In contrast, expression of glomerular endothelial and mesangial cell miRNAs (miR-126 and miR-145, respectively) was unchanged. These findings demonstrate a critical role for miRNA in glomerular function and suggest a pathway that may participate in the pathogenesis of kidney diseases of podocyte origin. The unique architecture of podocytes may make them especially susceptible to cytoskeletal alterations initiated by aberrant miRNA dynamics.

Dicer Cuts the Kidney

“…In this issue of JASN, three independent groups-Ho et al, Shi et al, and Harvey et al-report the phenotypes of mice with podocyte-specific genetic ablation of Dicer. [2][3][4] The overall goal of these three studies was to examine the impact of ablating Dicer activity, because it is key to miRNA production, on the phenotype of podocytes and, ultimately, glomerular and kidney function. Most endogenous miRNA function as a sophisticated conductor of genetic pathways by modifying the translational regulation of a number of genes at the same time.…”

“…All three groups identify members of the miR-30 miRNA family as kidney-specific and important players in the development of the observed phenotypes. [2][3][4] Shi et al 4 provide evidence that miRNA are involved in the regulation of apoptosis and cytoskeletal formation. Future studies should focus on identifying miRNA that are selectively expressed in specific kidney cell types, such as glomerular endothelial cells, podocytes, or proximal tubular renal epithelial cells.…”

“…Heterozygous mutant Dicer mice are, in general, phenotypically indistinguishable from wild-type counterparts under baseline conditions; however, Harvey et al note that mice carrying a disrupted Dicer gene in every cell of the body and one podocyte-disrupted allele (Dicer ⌬/fl ) exhibit a more severe phenotype than mice that carry two podocytedisrupted alleles (Dicer fl/fl ). 2 All three studies suggest that neighboring cell types become activated secondary to Dicerdependent podocyte injury. [2][3][4] Indeed, such secondary responses may be functionally important in mediating the progression of kidney disease and therefore warrant further investigation.…”

microRNAs in Diabetic Kidney Disease

“…As podocytes in the glomerular basement membrane are critical in maintaining the glomerular filtration barrier, podocyte dysfunction will lead to glomerular pathologies as in diabetic nephropathy (DN) or other types of glomerulonephritis [44]. Studies from mice with podocyte-specific deletion of Dicer [45][46][47] demonstrate that the loss of microRNAs resulted from deletion of Dicer leads to proteinuria, podocyte injury, and renal fibrosis. These results suggest the critical role of microRNAs in the podocytes to maintain the normal renal functions.…”

The Zebrafish Model to Study the Role of microRNAs in Glomerular Function and Disease

“…Different miRs have been found to be enriched in human kidneys include miR-192, miR-194, miR-204, miR-215 and miR-216 [11]. MiRs are also essential for podocyte homeostasis [12][13][14][15] and can be secreted in body fluids [16,17].…”