Inhibition of apoptosis signal-regulating kinase 1 mitigates the pathogenesis of human immunodeficiency virus-associated nephropathy.

Abstract

BACKGROUND:

Chronic kidney disease (CKD) is a common cause of morbidity and mortality in human immunodeficiency virus (HIV)-positive individuals. Among the HIV-related kidney diseases, HIV-associated nephropathy (HIVAN) is a rapidly progressive renal disease characterized by collapsing focal glomerulosclerosis (GS), microcystic tubular dilation, interstitial inflammation and fibrosis. Although the incidence of end-stage renal disease due to HIVAN has dramatically decreased with the widespread use of antiretroviral therapy, the prevalence of CKD continues to increase in HIV-positive individuals. Recent studies have highlighted the role of apoptosis signal-regulating kinase 1 (ASK1) in driving kidney disease progression through the activation of p38 mitogen-activated protein kinase and c-Jun N-terminal kinase and selective ASK-1 inhibitor GS-444217 was recently shown to reduce kidney injury and disease progression in various experimental models. Therefore we examined the efficacy of ASK1 antagonism by GS-444217 in the attenuation of HIVAN in Tg26 mice.

METHODS:

GS-444217-supplemented rodent chow was administered in Tg26 mice at 4 weeks of age when mild GS and proteinuria were already established. After 6 weeks of treatment, the kidney function assessment and histological analyses were performed and compared between age- and gender-matched control Tg26 and GS-444217-treated Tg26 mice.

RESULTS:

GS-444217 attenuated the development of GS, podocyte loss, tubular injury, interstitial inflammation and renal fibrosis in Tg26 mice. These improvements were accompanied by a marked reduction in albuminuria and improved renal function. Taken together, GS-4442217 attenuated the full spectrum of HIVAN pathology in Tg26 mice.

CONCLUSIONS:

ASK1 signaling cascade is central to the development of HIVAN in Tg26 mice. Our results suggest that the select inhibition of ASK1 could be a potential adjunctive therapy for the treatment of HIVAN.

• Authors: Anqun Chen, Jin Xu, Han Lai, Vivette D D'Agati, Tian-Jun Guan, Shawn Badal, John Liles, John C He, Kyung Lee
• Journal: Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association (Nephrol Dial Transplant) Vol. 36 Issue 3 Pg. 430-441 (02 20 2021) ISSN: 1460-2385 [Electronic] England
• PMID: 33097961 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © The Author(s) 2020. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.

Chemical References

• Protein Kinase Inhibitors
• MAP Kinase Kinase Kinase 5
• Map3k5 protein, mouse

Topics

• AIDS-Associated Nephropathy (drug therapy, metabolism, pathology)
• Animals
• Disease Models, Animal
• Fibrosis (prevention & control)
• Inflammation (prevention & control)
• MAP Kinase Kinase Kinase 5 (antagonists & inhibitors)
• Mice
• Mice, Transgenic
• Protein Kinase Inhibitors (pharmacology)
• Proteinuria (prevention & control)