Loss of Zeb2 in mesenchyme-derived nephrons causes primary glomerulocystic disease

Abstract

Primary glomerulocystic kidney disease is a special form of renal cystic disorder characterized by Bowman’s space dilatation in the absence of tubular cysts. ZEB2 is a SMAD-interacting transcription factor involved in Mowat-Wilson syndrome, a congenital disorder with an increased risk for kidney anomalies. Here we show that deletion of Zeb2 in mesenchyme-derived nephrons with either Pax2-cre or Six2-cre causes primary glomerulocystic kidney disease without tubular cysts in mice. Glomerulotubular junction analysis revealed many atubular glomeruli in the kidneys of Zeb2 knockout mice, which explains the presence of glomerular cysts in the absence of tubular dilatation. Gene expression analysis showed decreased expression of early proximal tubular markers in the kidneys of Zeb2 knockout mice preceding glomerular cyst formation, suggesting that defects in proximal tubule development during early nephrogenesis contribute to the formation of congenital atubular glomeruli. At the molecular level, Zeb2 deletion caused aberrant expression of Pkd1, Hnf1β, and Glis3, three genes causing glomerular cysts. Thus, Zeb2 regulates the morphogenesis of mesenchyme-derived nephrons and is required for proximal tubule development and glomerulotubular junction formation. Our findings also suggest that ZEB2 might be a novel disease gene in patients with primary glomerular cystic disease.

Exosomal miRNA-215-5p Derived from Adipose-Derived Stem Cells Attenuates Epithelial–Mesenchymal Transition of Podocytes by Inhibiting ZEB2

“…It has been demonstrated that ZEB2 expression promotes epithelial-to-mesenchymal transition (EMT) in renal cell carcinoma (RCC) and accumulated ZEB2 is an effective biomarker for the poor prognosis of patients with RCC [51]. Additionally, mice with a ZEB2specific deletion in metanephric mesenchyme led to primary glomerulocystic disease without tubular dilatation, which was absent in control mice, suggesting ZEB2 is required for proximal tubule development and normal glomerulotubular junction formation [52]. microRNAs have been found to be a regulator of ZEB2 and function as the EMT suppressor in many types of cells.…”

Transcriptomic profiling of tissue environments critical for post-embryonic patterning and morphogenesis of zebrafish skin

“…(B)Relative expression level of key marker genes as a function of pseudotime. zeb2 regulates mesenchymal progenitors in a variety of contexts(Hegarty et al, 2015;Rasouly et al, 2016;DaSilva-Arnold et al, 2019;Francescangeli et al, 2020). runx2 and sp7 regulate differentiation of amniote osteoblasts and odontoblasts(Jussila and Thesleff, 2012;Zhang, 2012;Bae et al, 2018).…”

lncRNA ZEB1-AS1 Was Suppressed by p53 for Renal Fibrosis in Diabetic Nephropathy

“…Several studies have demonstrated that the genetic deletion of ZEB1 and ZEB2 (another Zeb family gene) in mice can lead to renal fibrosis in vitro and kidney disease, respectively. 25 , 32 Hence, we postulated that HG induces renal fibrosis by downregulating lnc ZEB1-AS1 to suppress ZEB1 expression.…”