Targeting WIP1 phosphatase promotes partial remission in experimental collapsing glomerulopathy

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.