박선지 (Washington University School of Medicine, St. Louis, 현 대구경북첨단의료산업진흥재단) | 한빛사논문 > 한빛사

한빛사논문

조회715

Washington University School of Medicine, St. Louis, 현 대구경북첨단의료산업진흥재단

CV File 756 kb

Proc. Natl. Acad. Sci. USA, August 22, 2022 119 (35) e2116505119 | https://doi.org/10.1073/pnas.2116505119 Blocking CHOP-dependent TXNIP shuttling to mitochondria attenuates albuminuria and mitigates kidney injury in nephrotic syndrome

Sun-Ji Park^a, Yeawon Kim^a, Chuang Li^a, Junwoo Suh^b, Jothilingam Sivapackiam^c, Tassia M. Goncalves^d, George Jarad^a, Guoyan Zhao^d,e, Fumihiko Urano^f, Vijay Sharma^c,g,h,1, and Ying Maggie Chen^a,i,1

^aDivision of Nephrology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110;
^bDepartment of Biomedical Engineering, Case Western Reserve University, Cleveland, OH 44106;
^cMallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO 63110;
^dDepartment of Neuroscience, Washington University School of Medicine, St. Louis, MO 63110;
^eDepartment of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110;
^fDivision of Endocrinology, Metabolism, and Lipid Research, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110;
^gDepartment of Neurology, Washington University School of Medicine, St. Louis, MO 63110;
^hDepartment of Biomedical Engineering, School of Engineering & Applied Science, Washington University, St. Louis, MO 63105; and
ⁱDepartment of Cell Biology & Physiology, Washington University School of Medicine, St. Louis, MO 63110

¹To whom correspondence may be addressed.

Abstract

Albuminuria is a hallmark of glomerular disease of various etiologies. It is not only a symptom of glomerular disease but also a cause leading to glomerulosclerosis, interstitial fibrosis, and eventually, a decline in kidney function. The molecular mechanism underlying albuminuria-induced kidney injury remains poorly defined. In our genetic model of nephrotic syndrome (NS), we have identified CHOP (C/EBP homologous protein)-TXNIP (thioredoxin-interacting protein) as critical molecular linkers between albuminuria-induced ER dysfunction and mitochondria dyshomeostasis. TXNIP is a ubiquitously expressed redox protein that binds to and inhibits antioxidant enzyme, cytosolic thioredoxin 1 (Trx1), and mitochondrial Trx2. However, very little is known about the regulation and function of TXNIP in NS. By utilizing Chop^−/− and Txnip^−/− mice as well as ⁶⁸Ga-Galuminox, our molecular imaging probe for detection of mitochondrial reactive oxygen species (ROS) in vivo, we demonstrate that CHOP up-regulation induced by albuminuria drives TXNIP shuttling from nucleus to mitochondria, where it is required for the induction of mitochondrial ROS. The increased ROS accumulation in mitochondria oxidizes Trx2, thus liberating TXNIP to associate with mitochondrial nod-like receptor protein 3 (NLRP3) to activate inflammasome, as well as releasing mitochondrial apoptosis signal-regulating kinase 1 (ASK1) to induce mitochondria-dependent apoptosis. Importantly, inhibition of TXNIP translocation and mitochondrial ROS overproduction by CHOP deletion suppresses NLRP3 inflammasome activation and p-ASK1–dependent mitochondria apoptosis in NS. Thus, targeting TXNIP represents a promising therapeutic strategy for the treatment of NS.

논문정보

형식Research article
게재일2022년 08월 (BRIC 등록일 2022-09-02)
연구진국외 연구진
분야 의약학 > 분자세포의학

댓글 작성 로그인

CV 열람하기

연락처 보기