Inhibition of YAP activation attenuates renal injury and fibrosis in angiotensin II hypertensive mice

Abstract

Hippo/YAP (yes-associated protein) pathway is an important signaling pathway to control organ development and tissue homeostasis. YAP is a downstream effector of Hippo pathway and a critical mediator of mechanic stress. Hypertensive nephropathy is characterized with glomerular sclerosis stiffness and renal fibrosis. The present study investigated the role of YAP pathway in angiotensin (Ang) II hypertensive renal injury by using YAP activation inhibitor verteporfin. Ang II increased the protein expression of YAP in renal nucleus fraction, decreased p-YAP and p-LATS1/2 expressions in renal cytoplasmic fraction, suggesting Ang II activation of renal YAP. Ang II significantly increased systolic blood pressure (SBP), proteinuria, glomerular sclerosis and fibrosis, treatment with verteporfin attenuated Ang II-induced proteinuria and renal injury with a mild reduction in SBP. Moreover, Ang II increased the protein expressions of inflammatory factors including tumor necrosis factor α, interleukin 1β and monocyte chemoattractant protein-1, and profibrotic factors including transform growth factor β, phosphor-Smad3 and fibronectin. Verteporfin reversed Ang II-induced above-mentioned molecule expressions. Our results for the first time demonstrate that the activation of the YAP pathway promotes hypertensive renal inflammation and fibrosis, which may promote hypertensive renal injury. YAP may be a new target for prevention and treatment of hypertensive renal diseases.

Mechanisms underlying divergent relationships between Ca2+and YAP/TAZ signaling

“…Interestingly, in contrast to MST1/2-p, LATS1/2-p has only a higher steady-state level after Tg stimuli when compared to the initial concentration. In the case of Ang II stimulation, the LATS1/2-p steady-state level is lower than its initial level, indicating that Ang II has an inhibitory effect on LATS1/2 in the long term, similar to what has been observed in experimental studies 11,106 .…”

New Insights into Hippo/YAP Signaling in Fibrotic Diseases

“…Zhang et al showed that angiotensin (Ang) II-induced hypertensive renal injury promotes YAP activity, and causes increased proinflammatory and profibrotic factors including TNFα (tumor necrosis factor α), IL1β (interleukin 1β), MCP-1 (monocyte chemoattractant protein-1), TGF β, phospho-Smad3, and fibronectin. The blocking of YAP with verteporfin reversed AngII-induced renal inflammation and fibrosis [103]. The activation of YAP in RPTCs also drives renal interstitial fibrogenesis during diabetic neuropathy [33].…”

“…Renal fibrosis resulting from various renal injuries leads to progressive kidney damage and chronic kidney disease (CKD). Recent investigations reported that Hippo pathway components are crucial drivers of renal fibrosis [15,16,31,33,102,103]. Elevated YAP levels were reported in renal fibroblasts during interstitial fibrosis induced by unilateral ureteral obstruction (UUO) in mice [15].…”

“…An investigation demonstrated that conditional inactivation of the Hippo kinase Sav1 in renal tubule cells using Ksp CreER ;Sav1 fl/fl mice promoted renal interstitial fibrosis upon induction of AKI [36]. YAP activation was also found in nephropathy, a CKD characterized by glomerular sclerosis, stiffness and renal fibrosis [103]. Zhang et al showed that angiotensin (Ang) II-induced hypertensive renal injury promotes YAP activity, and causes increased proinflammatory and profibrotic factors including TNFα (tumor necrosis factor α), IL1β (interleukin 1β), MCP-1 (monocyte chemoattractant protein-1), TGF β, phospho-Smad3, and fibronectin.…”

Activation of Yes-Associated Protein/PDZ-Binding Motif Pathway Contributes to Endothelial Dysfunction and Vascular Inflammation in AngiotensinII Hypertension

“…The mice were randomly divided into the following three groups and treated for 3 weeks: (1) control (Ctr) group: the mice underwent sham procedures with the implantation of an empty osmotic mini-pump (n = 6); (2) AngII hypertensive group (AngII): the mice were implanted with an osmotic mini-pump (Alzet model 1002D, DURECT Inco., Cupertino, CA, United States) with the infusion of AngII (1.1 mg/kg/day, Sigma Aldrich, St. Louis, MO, United States, n = 6); (3) AngII with verteporfin treatment (AngII/Ve): the mice were implanted with an osmotic mini-pump with AngII plus verteporfin (Selleck, Houston, TX, United States) treatment (n = 6). We have previously shown that the mice that received the pressor dose of AngII for 5 days can develop hypertension and cardiovascular injury (Zhang et al, 2021). Verteporfin was dissolved in 10% of dimethylsulfoxide (DMSO) saline solution and administrated at a dosage of 60 mg/kg into mice by intraperitoneal injection every other day.…”