Background: Elevated Ang II (angiotensin II) level leads to a range of conditions, including hypertensive kidney disease. Recent evidences indicate that FGFR1 (fibroblast growth factor receptor 1) signaling may be involved in kidney injuries. In this study, we determined whether Ang II alters FGFR1 signaling to mediate renal dysfunction. Methods: Human archival kidney samples from patients with or without hypertension were examined. Multiple genetic and pharmacological approaches were used to investigate FGFR1-mediated signaling in tubular epithelial NRK-52E cells in response to Ang II stimulation. C57BL/6 mice were infused with Ang II for 28 days to develop hypertensive kidney disease. Mice were treated with either adeno-associated virus expressing FGFR1 shRNA or FGFR1 inhibitor AZD4547. Results: Kidney specimens from subjects with hypertension and mice challenged with Ang II have increased FGFR1 activity in renal epithelial cells. Renal epithelial cells in culture initiate extracellular matrix programming in response to Ang II, through the activation of FGFR1, which is independent of both AT1R (angiotensin II receptor type 1) and AT2R (angiotensin II receptor type 2). The RNA sequencing analysis indicated that disrupting FGFR1 suppresses Ang II–induced fibrogenic responses in epithelial cells. Mechanistically, Ang II–activated FGFR1 leads to STAT3 (signal transducer and activator of transcription 3) activation, which is responsible for fibrogenic factor expression in kidneys. In the mouse model of hypertensive kidney disease, genetic knockdown of FGFR1 or pharmacological inhibition of its activity protected kidneys from dysfunction and fibrosis upon Ang II challenge. Conclusions: Our studies uncover a novel mechanism causing renal fibrosis in hypertension and indicate FGFR1 as a potential target to preserve renal function and integrity.

Pancreatic adenocarcinoma is by far the deadliest type of cancer. Inflammation is one of the important risk factors in tumor development. However, it is not yet clear whether deterioration in pancreatic cancer patients is related to inflammation, as well as the underlying mechanism. In addition, JNK is abnormally activated in pancreatic cancer cells and the JNK inhibitor C66 reduces the inflammatory microenvironment in the tumor. Therefore, the aim of this study was to evaluate the role of C66 in the proliferation and migration of pancreatic cancer. Our results showed that various inflammatory cytokines, such as IL-1β, IL-6, IL-8, and IL-15, were more expressed in pancreatic cancer than in the matching normal tissue. Furthermore, C66, a curcumin analogue with good anti-inflammatory activity, inhibited the proliferation and migration of pancreatic cancer cells in a dose-dependent manner, and effectively inhibited the expression of the above inflammatory factors. Our previous research demonstrated that C66 prevents the inflammatory response by targeting JNK. Therefore, in this study, JNK activity in pancreatic cancer cells was investigated, revealing that JNK was highly activated, and the treatment with C66 inhibited the phosphorylation of JNK. Next, shJNK was used to knockdown JNK expression in pancreatic cancer cells to further confirm the role of JNK in the proliferation and migration of this tumor, as well as in the inflammatory tumor microenvironment (TME). The results demonstrated that JNK knockdown could significantly inhibit the proliferation and migration of pancreatic cancer. Moreover, the low JNK expression in pancreatic cancer cells significantly inhibited the expression of various inflammatory factors. These results indicated that C66 inhibited the progression of pancreatic cancer through the inhibition of JNK-mediated inflammation.

Background and Aims: Hypertensive heart failure has an urgent need for new therapeutic targets. Protein kinases act as key regulators in cellular actions relevant to cardiac pathophysiology. This study identified a protein kinase, Wee1 G2 checkpoint kinase (Wee1), being activated and involved in this disease. Methods: RNA-seq-based kinase enrichment analysis was used to identify the involved kinase pathways. Cardiomyocyte-specific Wee1-deficiency mice with chronic angiotensin II (Ang II) infusion and transverse aortic constriction (TAC) were utilized to develop cardiac remodelling. RNA-seq and co-immunoprecipitation were used to explore the mechanism and substrate of Wee1. Results: Kinase enrichment analysis and experimental evidence revealed that Wee1 phosphorylation at Ser642, but not increased expression, was observed in hypertrophic cardiac tissues from both mice and human patients. Knockdown, pharmacological inhibition, or mutational inactivation of Wee1 significantly alleviated Ang II-induced cardiomyocyte injuries. RNA-seq analysis showed that phosphoinositide 3-kinases/protein kinase B (AKT) pathway mediated the function of Wee1 in cardiomyocytes. Mechanistically, the phosphorylated Wee1 directly binds to the PHD domain of AKT to phosphorylate AKT inducing AKT/phosphoinositide 3-kinases–nuclear factor κB signalling pathway activation and subsequent inflammation and hypertrophy in cardiomyocytes. Cardiomyocyte-specific Wee1 deficiency was found to protect against cardiac inflammation, remodelling, and dysfunction in mice subjected to transverse aortic constriction or Ang II infusion. Pharmacological Wee1 inhibition also attenuated Ang II-induced cardiac remodelling in mice. Conclusions: Cardiomyocyte Wee1 activation drives inflammation and hypertrophy by directly phosphorylating AKT and activating AKT–nuclear factor κB pathway. This study identifies Wee1 as a new upstream kinase of AKT and a potential therapeutic target for hypertensive heart failure.