Abstract
The Wilms' tumor suppressor gene, WT1, encodes a zinc finger protein that regulates podocyte development and is highly expressed in mature podocytes. Mutations in the WT1 gene are associated with the development of renal failure due to the formation of scar tissue within glomeruli, the mechanisms of which are poorly understood. Here, we used a tamoxifen-based CRE-LoxP system to induce deletion of Wt1 in adult mice to investigate the mechanisms underlying evolution of glomerulosclerosis. Podocyte apoptosis was evident as early as the fourth day post-induction and increased during disease progression, supporting a role for Wt1 in mature podocyte survival. Podocyte Notch activation was evident at disease onset with upregulation of Notch1 and its transcriptional targets, including Nrarp. There was repression of podocyte FoxC2 and upregulation of Hey2 supporting a role for a Wt1/FoxC2/Notch transcriptional network in mature podocyte injury. The expression of cleaved Notch1 and HES1 proteins in podocytes of mutant mice was confirmed in early disease. Furthermore, induction of podocyte HES1 expression was associated with upregulation of genes implicated in epithelial mesenchymal transition, thereby suggesting that HES1 mediates podocyte EMT. Lastly, early pharmacological inhibition of Notch signaling ameliorated glomerular scarring and albuminuria. Thus, loss of Wt1 in mature podocytes modulates podocyte Notch activation, which could mediate early events in WT1-related glomerulosclerosis.
Highlights
G lomerulosclerosis accounts for 5% to 10% of pediatric and adult end-stage kidney disease and recurs in 15% to 30% of patients following kidney transplantation.[1]
Using an inducible model of Wilms’ tumor 1 (Wt1) deletion, we demonstrate a role for Notch activation in the pathogenesis of Wt1 glomerulopathy
We show that podocyte apoptosis is evident as early as the fourth day following tamoxifen administration to adult CAGGCreERTMþ/À;Wt1f/f transgenic mice before glomerulosclerosis is evident
Summary
G lomerulosclerosis accounts for 5% to 10% of pediatric and adult end-stage kidney disease and recurs in 15% to 30% of patients following kidney transplantation.[1]. Mutations in genes encoding transcription factors which regulate podocyte differentiation have been implicated in human glomerulosclerosis and include Wilms’ tumor 1 (WT1).[2,3,4,5,6,7] WT1 encodes a nuclear protein containing 4 zinc fingers that bind DNA and RNA and is highly expressed in mature podocytes.[8,9,10,11] Mutations in the regions involved in DNA binding or zinc finger formation have been reported in patients with Denys-Drash syndrome, a disorder associated with infantile diffuse mesangial sclerosis, gonadal dysgenesis, and Wilms’ tumor.[12,13,14] Mutations disrupting an alternative splice donor site in intron 9, results in Frasier syndrome, a disorder associated with focal segmental glomerulosclerosis (FSGS), predisposition to gonadoblastoma, and male pseudohermaphroditism.[15,16] mutations in WT1 have been reported in isolated primary steroid-resistant nephrotic syndrome, supporting a role for aberrant Wt1 function in the pathogenesis of glomerulosclerosis.[5,7]. Re-expression of Pax[2] in podocytes, cell cycle re-entry, and reduced expression of podocyte proteins such as nephrin and a-actinin-4 have been reported in heterozygous Wt1tmT396/þ mice with glomerulosclerosis by 8
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