Targeting WIP1 phosphatase promotes partial remission in experimental collapsing glomerulopathy
Collapsing focal segmental glomerulosclerosis (FSGS), also known as collapsing glomerulopathy (CG), is the most aggressive variant of FSGS and is characterized by rapid progression to end-stage kidney disease (ESKD). Understanding CG pathogenesis represents a key step for the development of targeted therapies. Previous work implicated the telomerase protein component TERT in CG pathogenesis, as transgenic TERT expression in adult mice resulted in a CG resembling that seen in human primary CG and HIV-associated nephropathy (HIVAN). We used the telomerase-induced mouse model of CG (i-TERTci mice) to identify mechanisms to inhibit CG pathogenesis. We found that inactivation of WIP1 phosphatase, a p53 target acting in a negative feedback loop, blocks disease initiation in i-TERTci mice. Repression of disease initiation upon WIP1 deficiency is associated with senescence enhancement and requires TGF-b functions. We further assessed efficacy of a pharmacologic treatment to reduce disease severity in both i-TERTci mice and in a mouse model of HIVAN (Tg26 mice). We found that pharmacologic inhibition of WIP1 enzymatic activity in either telomerase mice with CG or in Tg26 mice promotes partial remission of proteinuria and ameliorates renal histopathologic features. Histological as well as high throughput sequencing methods further showed that selective inhibition of WIP1 does not promote kidney fibrosis or inflammation. Our findings suggest that targeting WIP1 may be an effective therapeutic strategy for patients with CG. Overall design: To gain insight into the molecular factors and pathways modulated in i-TERTci mice treated with a selective inhibitor of WIP1 (GSK2830371) we performed high-throughput sequencing (bulk RNA-seq) analysis of total kidneys from DMSO- and GSK2830371-treated i-TERTci mice, and we compared transcriptomes of these mice to those of control single transgenic actin-rtTA+ mice.