Selective Dicer Suppression in the Kidney Alters GSK3β/β-Catenin Pathways Promoting a Glomerulocystic Disease

Abstract

Dicer is a crucial enzyme for the maturation of miRNAs. Mutations in the Dicer gene are highly associated with Pleuro Pulmonary Blastoma-Family Dysplasia Syndrome (PPB-FDS, OMIM 601200), recently proposed to be renamed Dicer syndrome. Aside from the pulmonary phenotype (blastoma), renal nephroma and thyroid goiter are frequently part of Dicer syndrome. To investigate the renal phenotype, conditional knockout (cKO) mice for Dicer in Pax8 expressing cells were generated. Dicer cKO mice progressively develop a glomerulocystic phenotype coupled with urinary concentration impairment, proteinuria and severe renal failure. Higher cellular turnover of the parietal cells of Bowman’s capsule precedes the development of the cysts and the primary cilium progressively disappears with cyst-enlargement. Upregulation of GSK3β precedes the development of the glomerulocystic phenotype. Downregulation of β-catenin in the renal cortex and its cytosolic removal in the cells lining the cysts may be associated with observed accumulation of GSK3β. Alterations of β-catenin regulating pathways could promote cystic degeneration as in other models. Thus, miRNAs are fundamental in preserving renal morphology and function. Alteration of the GSK3β/β-catenin pathway could be a crucial mechanism linking miRNA dysregulation and the development of a glomerulocystic disease.

NF-κB Essential Modulator (NEMO) Is Critical for Thyroid Function

“…Metabolic Measurements-Renal parameters were evaluated in 12-month-old mice using metabolic cages as described previously (19). Mice were housed individually in metabolic cages for 5 days at 23°C with a 12-h dark/light cycle.…”

Impact of Local and Systemic Factors on Kidney Dysfunction in Bardet-Biedl Syndrome

“…BBS proteins are required for targeting planary cell polarity (PCP) components to the basal body [52], raising the hypothesis of a role of BBS in PCP signaling. Recently we have identified the dysregulation of the PC in the glomerulocystic phenotype secondary to Dicer suppression [53]. Together with the impairment of the β-catenin/GSK3 β pathway this could be the underlying mechanism leading to the multi-organ cystic development in the Dicer syndrome.…”

MicroRNAs in Renal Diseases: A Potential Novel Therapeutic Target

“…So far, three different approaches have been followed to address the role of miRNAs in renal physiology: Suppression of Dicer gene expression is the most used model to investigate the role of miRNAs. In the kidney, Dicer conditional KO models have been generated for podocytes [19] , juxtaglomerular (JG) cells [20] , proximal tubules [21] , ureteric bud epithelium [22] , and overall epithelial cells of the nephron [23] ( Fig. 1 ).…”

“…In order to recapitulate the main alterations of the human Dicer syndrome, we suppressed Dicer expression in the epithelial cell of the kidney and thyroid by generating a Dicer floxed -Pax8 CRE mouse model [23] . This mouse model develops multiple cysts in the kidneys and thyroid, resembling the goiter and the renal nephroma crucial traits of the Dicer syndrome [3] .…”

“…We showed that higher cellular turnover of the parietal cells of Bowman's capsule precedes the development of the cysts and that the enlargement of the Bowman's space was associated with progressive disappearance of the primary cilium. As molecular determinant of the Dicer induced cystogenesis, we identified a dysregulation of the of GSK3β/β-catenin pathways [23] . Indeed, severe downregulation of β-catenin and cytosolic retention was observed in cKO mice, and this was paralleled by alteration in GSK3β expression.…”