Tubular MST1/2 Deletion and Renal Fibrosis

EDITORIAL www.jasn.org

Tubular MST1/2 Deletion and in kidney disease and regeneration. In mouse models for diabetes type 1 and type 2, increased YAP expression was Renal Fibrosis observed in proximal tubular cells.8 This upregulation was in- hibited in mice with deletion of epidermal growth factor re- Monica Chang-Panesso ceptor (EGFR) in proximal tubule or when treated with the Division of Nephrology, Department of Medicine, Washington EGFR inhibitor erlotinib, therefore suggesting an interaction University in St. Louis School of Medicine, St. Louis, Missouri between EGFR and the Hippo pathway. Furthermore, in vitro

JASN 31: ccc–ccc, 2020. studies in proximal tubular cells exposed to high glucose had doi: https://doi.org/10.1681/ASN.2020030305 increased YAP expression along with upregulation of profibrotic genes connective tissue growth factor (CTGF) and am- phiregulin (AREG). After treatment with erlotinib, these cells Renal fibrosis is one of the underlying processes behind CKD decreased YAPexpression as well as CTGF and AREG expression, progression. Understanding what the molecular mechanisms suggesting that YAP activation via EGFR could drive fibrosis in are that drive and sustain fibrosis is key to develop treatment diabetic nephropathy. Another group using in vitro and in vivo strategies. The Hippo pathway has been implicated in promot- animal models demonstrated that treatment with verteporfin, ing fibrosis in several organs, including the kidney.1 In this a YAP-TEAD inhibitor, attenuated renal fibrosis probably by in- issue of JASN,Xuet al.2 present evidence that tubular YAP terfering with the crosstalk between YAP/TAZ and TGF-b/Smad activation induces renal fibrosis. in fibroblasts, thus also highlighting a possible pathogenic role The Hippo pathway is a signal transduction pathway widely for the Hippo pathway.9 In contrast, another study showed that studied in the context of organ development and cancer given YAP is activated after ischemic renal injury in mice and that this its role in control of organ size, cell proliferation, and cell process is mediated via the EGFR-PI3K-Akt pathway. YAP in- survival. Core genes of this pathway were first reported in hibition using verteporfin caused delayed renal recovery, suggest- Drosophila melanogaster in independent studies in the mid- ing that YAP activation is an important step in tubular epithelial 1990s to early 2000s; however, it was not until 2005 when it repair after renal injury.10 was formally described as a pathway involved in the regulation Xu et al.2 present a well designed study using a very demanding of cell proliferation and apoptosis.3 A couple of years later, in breeding strategy to generate double- and triple-knockout mouse 2007, the mammalian Hippo pathway was delineated and es- models for MST1/MST2 and MST1/MST2/YAP in tubular tablished as a universal regulator of organ size.4 In the same epithelial cells using the Ksp-Cre driver. They showed that year, a group created a null mouse model for TAZ, a down- tubular-specific deletion of MST1/MST2 in tubular epithelial cells stream effector of the Hippo pathway, and found that this led to an increase in YAP expression associated with renal fibrosis mouse displayed cystic kidneys and developed progressive re- and functional impairment. Given the potentially profibrotic role nal failure.5 This was probably one of the first studies bringing for YAP activation in tubular epithelial cells, they then induced to light the relevance of the Hippo pathway in the kidney field, YAP deletion and were able to rescue the phenotype, providing especially because embryonic deletion of one of its effector evidence that indeed tubular YAP can mediate a fibrotic response genes (TAZ ) led to a cystic kidney disease phenotype. Since in the kidney. Furthermore, they identified that MST1/2 deletion then, further studies using animal models and validation in hu- causes an increase in TNF-a expression. Through in vitro and in man specimens have provided evidence that the Hippo pathway vivo experiments, they showed that TNF-a activates YAP, and is implicated in cystogenesis and the development of polycystic a positive feedback loop may exist between them that ultimately kidney disease. In subsequent years, it was described that the contributes to renal fibrosis. Hippo pathway has a role in nephrogenesis and lower urinary This study joins the work of others describing YAP as a me- tract development,6,7 adding further support to the involvement diator of renal fibrosis. The authors’ approach is elegant: tar- of this pathway in kidney development and disease. geting deletion of one of the core Hippo upstream genes Over the past 5 years, a growing body of evidence has accu- (MST1/2) specifically in tubular epithelial cells and corrobo- mulated describing multifaceted roles for the Hippo pathway rating that the observed fibrotic phenotype was mediated through YAP by rescuing the phenotype via YAP deletion. Despite less MST1/2 deletion in the proximal tubular segment, Published online ahead of print. Publication date available at www.jasn.org. likely due to decrease recombination efficiency in this segment Correspondence: Dr. Monica Chang-Panesso, Division of Nephrology, by the Ksp-Cre driver, it is interesting to observe that there was Washington University School of Medicine, 660 South Euclid Avenue CB 8126, acomparabledegreeoffibrosis in the cortex and medulla. St. Louis, MO 63110. Email: [email protected] This result suggests that a lower threshold of tubular YAP Copyright © 2020 by the American Society of Nephrology activation is required to cause fibrosis in the cortex. It is also

JASN 31: ccc–ccc,2020 ISSN : 1046-6673/3105-ccc 1 EDITORIAL www.jasn.org surprising that there are observed sex difference, with females 2. Xu C, Wang L, Zhang Y, Li W, Li J, Wang Y, et al.: Tubule-specific Mst1/2 having an attenuated fibrotic response after MST1/2 deletion. deficiency induces chronic kidney disease via YAP and non-YAP J Am Soc Nephrol – Their results aligns with the recent findings from Harris and col- mechanisms. 31: XXX XXX, 2020 3. Huang J, Wu S, Barrera J, Matthews K, Pan D: The Hippo signaling 11 leagues, wheretheyobservedthatfemalemicewithagainof pathway coordinately regulates cell proliferation and apoptosis by in- function in EGFR displayed less renal injury and fibrosis com- activating Yorkie, the Drosophila Homolog of YAP. Cell 122: 421–434, pared with their male counterparts. One could hypothesize on the 2005 basis of previous studies from the group of Harris and colleagues11 4. Dong J, Feldmann G, Huang J, Wu S, Zhang N, Comerford SA, et al.: linking EGFR and the Hippo pathway that EGFR-mediated YAP Elucidation of a universal size-control mechanism in Drosophila and mammals. Cell 130: 1120–1133, 2007 activationinfemalesislessdetrimental.Perhapsfurtherstudies 5. Hossain Z, Ali SM, Ko HL, Xu J, Ng CP, Guo K, et al.: Glomerulocystic could help establish this connection. kidney disease in mice with a targeted inactivation of Wwtr1. Proc Natl In summary, the study by Xu et al.2 provides evidence Acad Sci U S A 104: 1631–1636, 2007 for the Hippo pathway as a mediator of renal fibrosis. It will be 6. Reginensi A, Scott RP, Gregorieff A, Bagherie-Lachidan M, Chung C, important to reconcile with future experiments if there is Lim DS, et al.: Yap- and Cdc42-dependent nephrogenesis and morphogenesis during mouse kidney development. PLoS Genet 9: a level of balance in YAP activation, whereby it plays a crucial e1003380, 2013 role in renal regeneration, but overactivation might lead to 7. Reginensi A, Hoshi M, Boualia SK, Bouchard M, Jain S, McNeill H: Yap renal fibrosis, possible due to maladaptive repair. and Taz are required for Ret-dependent urinary tract morphogenesis. Development 142: 2696–2703, 2015 8. Chen J, Harris RC: Interaction of the EGF receptor and the Hippo DISCLOSURES pathway in the diabetic kidney. J Am Soc Nephrol 27: 1689–1700, 2016 9. Szeto SG, Narimatsu M, Lu M, He X, Sidiqi AM, Tolosa MF, et al.: None. YAP/TAZ are mechanoregulators of TGF-b-Smad signaling and renal fibrogenesis. JAmSocNephrol27: 3117–3128, 2016 10. Chen J, You H, Li Y, Xu Y, He Q, Harris RC: EGF receptor-dependent FUNDING YAP activation is important for renal recovery from AKI. JAmSoc Nephrol 29: 2372–2385, 2018 11. Zhang MZ, Sasaki K, Li Y, Li Z, Pan Y, Jin GN, et al.: The role of the EGF None. receptor in sex differences in kidney injury. JAmSocNephrol30: 1659–1673, 2019 REFERENCES

1. Moya IM, Halder G: Hippo-YAP/TAZ signalling in organ regeneration See related article, “Tubule-SpeciﬁcMst1/2Deﬁciency Induces CKD via YAP and and regenerative medicine. Nat Rev Mol Cell Biol 20: 211–226, 2019 Non-YAP Mechanisms,” on pages XXX–XXX.

2 JASN JASN 31: ccc–ccc,2020