Epithelial Vasopressin Type-2 Receptors Regulate Myofibroblasts by a YAP-CCN2–Dependent Mechanism in Polycystic Kidney Disease

Abstract

BackgroundFibrosis is a major cause of loss of renal function in autosomal dominant polycystic kidney disease (ADPKD). In this study, we examined whether vasopressin type-2 receptor (V2R) activity in cystic epithelial cells can stimulate interstitial myofibroblasts and fibrosis in ADPKD kidneys.MethodsWe treated Pkd1 gene knockout (Pkd1KO) mice with dDAVP, a V2R agonist, for 3 days and evaluated the effect on myofibroblast deposition of extracellular matrix (ECM). We also analyzed the effects of conditioned media from primary cultures of human ADPKD cystic epithelial cells on myofibroblast activation. Because secretion of the profibrotic connective tissue growth factor (CCN2) increased significantly in dDAVP-treated Pkd1KO mouse kidneys, we examined its role in V2R-dependent fibrosis in ADPKD as well as that of yes-associated protein (YAP).ResultsV2R stimulation using dDAVP increased the renal interstitial myofibroblast population and ECM deposition. Similarly, conditioned media from human ADPKD cystic epithelial cells increased myofibroblast activation in vitro, suggesting a paracrine mechanism. Renal collecting duct–specific gene deletion of CCN2 significantly reduced cyst growth and myofibroblasts in Pkd1KO mouse kidneys. We found that YAP regulates CCN2, and YAP inhibition or gene deletion reduces renal fibrosis in Pkd1KO mouse kidneys. Importantly, YAP inactivation blocks the dDAVP-induced increase in myofibroblasts in Pkd1KO kidneys. Further in vitro studies showed that V2R regulates YAP by an ERK1/2-dependent mechanism in human ADPKD cystic epithelial cells.ConclusionsOur results demonstrate a novel mechanism by which cystic epithelial cells stimulate myofibroblasts in the pericystic microenvironment, leading to fibrosis in ADPKD. The V2R-YAP-CCN2 cell signaling pathway may present a potential therapeutic target for fibrosis in ADPKD.

Transfer learning of an in vivo-derived senescence signature identifies conserved and tissue-specific senescence across species and diverse pathologies

“…The CCN matricellular proteins have been implicated in induction of senescence in a variety of contexts (Joon-Il Jun & Lau, 2011; Joon-II Jun & Lau, 2017; Valentijn et al, 2021). They are also regulatory targets of the YAP/TAZ pathway, a mechanosensing pathway recently highlighted for its potential role in fibrosis (Dwivedi et al, 2020; Mascharak et al, 2022; Zhou et al, 2022). Activation of YAP was associated with increased fibrosis, increased expression of CSF1 leading to myeloid-derived inflammation, and increased expression of CCN family members.…”

Age-Related Downregulation of CCN2 Is Regulated by Cell Size in a YAP/TAZ-Dependent Manner in Human Dermal Fibroblasts: Impact on Dermal Aging

“…Shome et al recently reported that dermal fibroblasts activation of YAP stimulates CCN2 secretion, which in turn through paracrine signaling activates keratinocytes, accelerate migration, and promote wound healing (Shome et al, 2020). Conversely, cystic epithelial cells stimulate myofibroblast activation in the pericystic microenvironment leading to fibrosis through activation of YAP and stimulation of CCN2 expression (Dwivedi et al, 2020). It also should be noted that YAP/TAZ-CCN2 axis may function as an important mediator in fibrosis through myofibroblast activation and ECM production.…”

Polycystin‐1 and hydrostatic pressure are implicated in glioblastoma pathogenesis in vitro

“…Based on our previous results regarding the modulation of intracellular signalling pathways by PC1 and HP in GBM cells, we wondered whether PC1 blockade and/or HP may also affect the levels of proteins involved in the regulation of gene transcription within the GBM cell nucleus. Specifically, we decided to focus on two well‐known mechano‐induced transcription cofactors, namely, YAP and TAZ because both have been identified as mediators of PC1‐dependent mechanotransduction 31–35 and are implicated in GBM pathogenesis 36 5).…”