Abstract: TH-PO075

Apoptosis Signal-Regulating Kinase 1 (ASK1) Inhibitor GS-444217 Mitigates Progression of HIV-Associated Nephropathy

Session Information

Category: Glomerular

  • 1002 Glomerular: Basic/Experimental Pathology

Authors

  • Lee, Kyung, Icahn School of Medicine at Mount Sinai, New York, New York, United States
  • Xu, Jin, Icahn School of Medicine at Mount Sinai, New York, New York, United States
  • Chen, Anqun, Icahn School of Medicine at Mount Sinai, New York, New York, United States
  • Liles, John T., Gilead Sciences, Inc., Foster City, California, United States
  • He, John C., Icahn School of Medicine at Mount Sinai, New York, New York, United States
Background

Renal inflammation is the major pathology in chronic kidney diseases, including HIV-associated nephropathy (HIVAN) that ultimately progresses to end stage renal disease. Activation of apoptosis signal-regulating kinase 1(ASK1) has been shown to drive renal inflammation, apoptosis, and fibrosis by downstream activation of MAPK kinases p38 and c-Jun N terminal kinase (JNK). Recent studies have shown that a potent selective ASK1 inhibitor substantially reduced renal p38MAPK activation and halted the disease progression in mouse models of diabetic kidney disease. Thus we sought to determine whether the blockade of ASK1 would also attenuate renal injury and impede the progression of HIVAN.

Methods

A well-established transgenic model of HIVAN, Tg26 mice on FVB/N background, was used for the study. Tg26 mice typically start to develop proteinuria and mild glomerulosclerosis (GS) at 4 weeks of age, moderate GS and mild tubulointerstitial injury by 8 weeks of age, and advanced GS and tubulointerstitial fibrosis, tubular atrophy and dilatation by 12 weeks of age. 4-week old Tg26 mice received either standard control chow or chow supplemented with selective ASK1 inhibitor GS-444217 (0.1% or 0.2% in chow). There were 7 to 10 mice in each group. Urine and blood were collected weekly to assess their kidney functions, and kidneys were harvested for analysis after 6 weeks of treatment.

Results

Administration of ASK1 inhibitor GS-444217 at both 0.1% and 0.2% concentrations significantly reduced p38 activation and albuminuria, and improved renal function in Tg26 mice after 6 weeks of treatment. Histological analysis revealed a marked reduction in GS and tubular damage in mice treated with GS-444217 compared to control Tg26 mice. GS-444217 administration increased the expression of differentiated podocytes markers and significantly curtailed podocyte loss in Tg26 mice. GS-444217 also reduced marker expressions of inflammation and apoptosis. Furthermore, GS-444217 administration resulted in significant reduction in collagen deposition and renal fibrosis.

Conclusion

Selective ASK1 inhibition reduced both glomerular and tubular injury and mitigated the progression of HIVAN in Tg26 mice, suggesting that blockade of ASK1 pathway is a potential therapeutic approach against progression of CKD, including HIVAN.

Funding

  • Commercial Support