title: TGF-β-activated kinase 1 is crucial in podocyte differentiation and glomerular capillary formation.
abstract: TGF-β-activated kinase 1 (TAK1) is a key intermediate in signal transduction induced by TGF-β or inflammatory cytokines, such as TNF-α and IL-1, which are potent inducers of podocyte injury responses that lead to proteinuria and glomerulosclerosis. Nevertheless, little is known about the physiologic and pathologic roles of TAK1 in podocytes. To examine the in vivo role of TAK1, we generated podocyte-specific Tak1 knockout mice (Nphs2-Cre(+):Tak1(fx/fx); Tak1(∆/∆)). Targeted deletion of Tak1 in podocytes resulted in perinatal lethality, with approximately 50% of animals dying soon after birth and 90% of animals dying within 1 week of birth. Tak1(∆/∆) mice developed proteinuria from P1 and exhibited delayed glomerulogenesis and reduced expression of Wilms' tumor suppressor 1 and nephrin in podocytes. Compared with Tak1(fx/fx) mice, Tak1(∆/∆) mice exhibited impaired formation of podocyte foot processes that caused disruption of the podocyte architecture with prominent foot process effacement. Intriguingly, Tak1(∆/∆) mice displayed increased expression of vascular endothelial growth factor within the glomerulus and abnormally enlarged glomerular capillaries. Furthermore, 4- and 7-week-old Tak1(∆/∆) mice with proteinuria had increased collagen deposition in the mesangium and the adjacent tubulointerstitial area. Thus, loss of Tak1 in podocytes is associated with the development of proteinuria and glomerulosclerosis. Taken together, our data show that TAK1 regulates the expression of Wilms' tumor suppressor 1, nephrin, and vascular endothelial growth factor and that TAK1 signaling has a crucial role in podocyte differentiation and attainment of normal glomerular microvasculature during kidney development and glomerular filtration barrier homeostasis.
authors.affiliation: Renal Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts; Division of Nephrology and Hypertension, Weill Cornell Medical College, New York, New York; szk2006@med.cornell.edu mechoi@med.cornell.edu.
authors.forename: Sung Il
authors.initials: SI
authors.lastname: Kim
authors.affiliation: Renal Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts; Department of Internal Medicine, Bundang CHA Medical Center, CHA University School of Medicine, Seongnam, South Korea; and.
authors.forename: So-Young
authors.initials: SY
authors.lastname: Lee
authors.affiliation: Renal Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts;
authors.forename: Zhibo
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Renal Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts; Division of Nephrology and Hypertension, Weill Cornell Medical College, New York, New York;
authors.forename: Yan
authors.initials: Y
authors.lastname: Ding
authors.affiliation: Renal Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts;
authors.forename: Nadeem
authors.initials: N
authors.lastname: Haque
authors.affiliation: Oncology Institute, Cardinal Bernardin Cancer Center, Department of Pathology, Loyola University Medical Center, Maywood, Illinois.
authors.forename: Jiwang
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Renal Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts;
authors.forename: Jing
authors.initials: J
authors.lastname: Zhou
authors.affiliation: Renal Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts; Division of Nephrology and Hypertension, Weill Cornell Medical College, New York, New York; szk2006@med.cornell.edu mechoi@med.cornell.edu.
authors.forename: Mary E
authors.initials: ME
authors.lastname: Choi
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D002196:Capillaries / Q000201:enzymology / Q000254:growth & development; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology; D003094:Collagen / Q000378:metabolism; D005260:Female; D060730:Glomerular Filtration Barrier / Q000098:blood supply / Q000201:enzymology / Q000254:growth & development; D007678:Kidney Glomerulus / Q000098:blood supply* / Q000201:enzymology* / Q000254:growth & development; D020930:MAP Kinase Kinase Kinases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D050199:Podocytes / Q000166:cytology* / Q000201:enzymology*; D011247:Pregnancy; D011507:Proteinuria / Q000201:enzymology / Q000209:etiology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism; D025721:WT1 Proteins / Q000235:genetics / Q000378:metabolism; D000099151:MAP Kinase Kinase Kinase 7
chemical_list: D003094:Collagen; D020930:MAP Kinase Kinase Kinases; D008565:Membrane Proteins; D012333:RNA, Messenger; D042461:Vascular Endothelial Growth Factor A; D025721:WT1 Proteins; D000099151:MAP Kinase Kinase Kinase 7; C113267:nephrin; C467480:vascular endothelial growth factor A, mouse