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Targeting WIP1 phosphatase promotes partial remission in experimental collapsing glomerulopathy
Lou C Duret1, Tynhinane Hamidouche1, Nicholas J Steers2
1Université Côte d'Azur (UCA), Centre National de la Recherche Scientifique (CNRS) UMR7284, Institut National de la Santé et de la Recherche Médicale (Inserm) U1081, Institute for Research on Cancer and aging, Nice (IRCAN), Nice, France.
Abstract:
Collapsing focal segmental glomerulosclerosis (FSGS), also known as collapsing glomerulopathy (CG), is the most aggressive variant of FSGS and is characterized by a rapid progression to kidney failure. 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). Here, we used the telomerase-induced mouse model of CG (i-TERTci mice) to identify mechanisms to inhibit CG pathogenesis. Inactivation of WIP1 phosphatase, a p53 target acting in a negative feedback loop, blocked disease initiation in i-TERTci mice. Repression of disease initiation upon WIP1 deficiency was associated with senescence enhancement and required transforming growth factor-β functions. The efficacy of a pharmacologic treatment to reduce disease severity in both i-TERTci mice and in a mouse model of HIVAN (Tg26 mice) was then assessed. Pharmacologic inhibition of WIP1 enzymatic activity in either the telomerase mice with CG or in the Tg26 mice promoted partial remission of proteinuria and ameliorated kidney histopathologic features. Histological as well as high-throughput sequencing methods further showed that selective inhibition of WIP1 does not promote kidney fibrosis or inflammation. Thus, our findings suggest that targeting WIP1 may be an effective therapeutic strategy for patients with CG.
Insights
Targeting WIP1 phosphatase inhibits aggressive kidney disease progression in collapsing glomerulopathy (CG) and HIV-associated nephropathy (HIVAN) models. This approach offers a potential new therapy for patients with these conditions.
Area of Science:
- Nephrology
- Molecular Biology
- Pathogenesis of Kidney Disease
Background:
- Collapsing focal segmental glomerulosclerosis (FSGS), or collapsing glomerulopathy (CG), is an aggressive kidney disease variant with rapid progression to kidney failure.
- Previous research implicated telomerase (TERT) in CG pathogenesis, with transgenic TERT expression inducing CG-like pathology in mice.
Purpose of the Study:
- To identify mechanisms to inhibit CG pathogenesis using a telomerase-induced mouse model (i-TERTci).
- To evaluate the therapeutic potential of targeting WIP1 phosphatase in CG and HIV-associated nephropathy (HIVAN).
Main Methods:
- Utilized the telomerase-induced mouse model of CG (i-TERTci mice) and a mouse model of HIVAN (Tg26 mice).
- Assessed the effects of WIP1 phosphatase inactivation and pharmacologic inhibition on disease initiation and progression.
- Employed histological and high-throughput sequencing methods to analyze kidney pathology and molecular changes.
Main Results:
- Inactivation of WIP1 phosphatase blocked CG disease initiation in i-TERTci mice, associated with enhanced senescence and transforming growth factor-β functions.
- Pharmacologic inhibition of WIP1 enzymatic activity reduced proteinuria and improved kidney histopathology in both i-TERTci and Tg26 mice.
- Selective WIP1 inhibition did not promote kidney fibrosis or inflammation.
Conclusions:
- Targeting WIP1 phosphatase represents a promising therapeutic strategy for collapsing glomerulopathy (CG) and HIV-associated nephropathy (HIVAN).
- Pharmacologic inhibition of WIP1 may offer a novel treatment approach to ameliorate kidney disease severity and progression.
