Tubular MST1/2 Deletion and Renal Fibrosis
Authors: Monica Chang-Panesso
Journal: Journal of the American Society of Nephrology (2020)

Renal fibrosis is one of the underlying processes behind CKD progression. Understanding what the molecular mechanisms are that drive and sustain fibrosis is key to develop treatment strategies. The Hippo pathway has been implicated in promoting fibrosis in several organs, including the kidney.1 In this issue of JASN, Xu et al.2 present evidence that tubular YAP activation induces renal fibrosis. The Hippo pathway is a signal transduction pathway widely studied in the context of organ development and cancer given its role in control of organ size, cell proliferation, and cell survival. Core genes of this pathway were first reported in Drosophila melanogaster in independent studies in the mid-1990s to early 2000s; however, it was not until 2005 when it was formally described as a pathway involved in the regulation of cell proliferation and apoptosis.3 A couple of years later, in 2007, the mammalian Hippo pathway was delineated and established as a universal regulator of organ size.4 In the same year, a group created a null mouse model for TAZ, a downstream effector of the Hippo pathway, and found that this mouse displayed cystic kidneys and developed progressive renal failure.5 This was probably one of the first studies bringing to light the relevance of the Hippo pathway in the kidney field, especially because embryonic deletion of one of its effector genes (TAZ) led to a cystic kidney disease phenotype. Since then, further studies using animal models and validation in human specimens have provided evidence that the Hippo pathway is implicated in cystogenesis and the development of polycystic kidney disease. In subsequent years, it was described that the Hippo pathway has a role in nephrogenesis and lower urinary tract development,6,7 adding further support to the involvement of this pathway in kidney development and disease. Over the past 5 years, a growing body of evidence has accumulated describing multifaceted roles for the Hippo pathway in kidney disease and regeneration. In mouse models for diabetes type 1 and type 2, increased YAP expression was observed in proximal tubular cells.8 This upregulation was inhibited in mice with deletion of epidermal growth factor receptor (EGFR) in proximal tubule or when treated with the EGFR inhibitor erlotinib, therefore suggesting an interaction between EGFR and the Hippo pathway. Furthermore, in vitro studies in proximal tubular cells exposed to high glucose had increased YAP expression along with upregulation of profibrotic genes connective tissue growth factor (CTGF) and amphiregulin (AREG). After treatment with erlotinib, these cells decreased YAP expression as well as CTGF and AREG expression, suggesting that YAP activation via EGFR could drive fibrosis in diabetic nephropathy. Another group using in vitro and in vivo animal models demonstrated that treatment with verteporfin, a YAP-TEAD inhibitor, attenuated renal fibrosis probably by interfering with the crosstalk between YAP/TAZ and TGF-β/Smad in fibroblasts, thus also highlighting a possible pathogenic role for the Hippo pathway.9 In contrast, another study showed that YAP is activated after ischemic renal injury in mice and that this process is mediated via the EGFR-PI3K-Akt pathway. YAP inhibition using verteporfin caused delayed renal recovery, suggesting that YAP activation is an important step in tubular epithelial repair after renal injury.10 Xu et al.2 present a well designed study using a very demanding breeding strategy to generate double- and triple-knockout mouse models for MST1/MST2 and MST1/MST2/YAP in tubular epithelial cells using the Ksp-Cre driver. They showed that tubular-specific deletion of MST1/MST2 in tubular epithelial cells led to an increase in YAP expression associated with renal fibrosis and functional impairment. Given the potentially profibrotic role for YAP activation in tubular epithelial cells, they then induced YAP deletion and were able to rescue the phenotype, providing evidence that indeed tubular YAP can mediate a fibrotic response in the kidney. Furthermore, they identified that MST1/2 deletion causes an increase in TNF-α expression. Through in vitro and in vivo experiments, they showed that TNF-α activates YAP, and a positive feedback loop may exist between them that ultimately contributes to renal fibrosis. This study joins the work of others describing YAP as a mediator of renal fibrosis. The authors’ approach is elegant: targeting deletion of one of the core Hippo upstream genes (MST1/2) specifically in tubular epithelial cells and corroborating 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, likely due to decrease recombination efficiency in this segment by the Ksp-Cre driver, it is interesting to observe that there was a comparable degree of fibrosis in the cortex and medulla. This result suggests that a lower threshold of tubular YAP activation is required to cause fibrosis in the cortex. It is also surprising that there are observed sex difference, with females having an attenuated fibrotic response after MST1/2 deletion. Their results aligns with the recent findings from Harris and colleagues,11 where they observed that female mice with a gain of function in EGFR displayed less renal injury and fibrosis compared with their male counterparts. One could hypothesize on the basis of previous studies from the group of Harris and colleagues11 linking EGFR and the Hippo pathway that EGFR-mediated YAP activation in females is less detrimental. Perhaps further studies could help establish this connection. In summary, the study by Xu et al.2 provides evidence for the Hippo pathway as a mediator of renal fibrosis. It will be important to reconcile with future experiments if there is a level of balance in YAP activation, whereby it plays a crucial role in renal regeneration, but overactivation might lead to renal fibrosis, possible due to maladaptive repair. Disclosures None. Funding None.