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TP53RK Drives the Progression of Chronic Kidney Disease by Phosphorylating Birc5.

ABSTRACT: Renal fibrosis is a common characteristic of various chronic kidney diseases (CKDs) driving the loss of renal function. During this pathological process, persistent injury to renal tubular epithelial cells and activation of fibroblasts chiefly determine the extent of renal fibrosis. In this study, the role of tumor protein 53 regulating kinase (TP53RK) in the pathogenesis of renal fibrosis and its underlying mechanisms is investigated. TP53RK is upregulated in fibrotic human and animal kidneys with a positive correlation to kidney dysfunction and fibrotic markers. Interestingly, specific deletion of TP53RK either in renal tubule or in fibroblasts in mice can mitigate renal fibrosis in CKD models. Mechanistic investigations reveal that TP53RK phosphorylates baculoviral IAP repeat containing 5 (Birc5) and facilitates its nuclear translocation; enhanced Birc5 displays a profibrotic effect possibly via activating PI3K/Akt and MAPK pathways. Moreover, pharmacologically inhibiting TP53RK and Birc5 using fusidic acid (an FDA-approved antibiotic) and YM-155(currently in clinical phase 2 trials) respectively both ameliorate kidney fibrosis. These findings demonstrate that activated TP53RK/Birc5 signaling in renal tubular cells and fibroblasts alters cellular phenotypes and drives CKD progression. A genetic or pharmacological blockade of this axis serves as a potential strategy for treating CKDs.

SUBMITTER: Wu M

PROVIDER: S-EPMC10477881 | biostudies-literature | 2023 Sep

REPOSITORIES: biostudies-literature

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TP53RK Drives the Progression of Chronic Kidney Disease by Phosphorylating Birc5.

Wu Mengqiu M Jin Qianqian Q Xu Xinyue X Fan Jiaojiao J Chen Weiyi W Miao Mengqiu M Gu Ran R Zhang Shengnan S Guo Yan Y Huang Songming S Zhang Yue Y Zhang Aihua A Jia Zhanjun Z

Advanced science (Weinheim, Baden-Wurttemberg, Germany) 20230629 25

Renal fibrosis is a common characteristic of various chronic kidney diseases (CKDs) driving the loss of renal function. During this pathological process, persistent injury to renal tubular epithelial cells and activation of fibroblasts chiefly determine the extent of renal fibrosis. In this study, the role of tumor protein 53 regulating kinase (TP53RK) in the pathogenesis of renal fibrosis and its underlying mechanisms is investigated. TP53RK is upregulated in fibrotic human and animal kidneys w ...[more]

PMID: 37382161

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Project description:Chronic kidney disease (CKD) has been recognized as a leading public health problem worldwide. Through its effect on cardiovascular risk and end-stage kidney disease, CKD directly affects the global burden of morbidity and mortality. Classical optimal management of CKD includes blood pressure control, treatment of albuminuria with angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers, avoidance of potential nephrotoxins and obesity, drug dosing adjustments, and cardiovascular risk reduction. Diabetes might account for more than half of CKD burden, and obesity is the most important prompted factor for this disease. New antihyperglycemic drugs, such as sodium-glucose-cotransporter 2 inhibitors have shown to slow the decline of GFR, bringing additional benefit in weight reduction, cardiovascular, and other kidney outcomes. On the other hand, a new generation of non-steroidal mineralocorticoid receptor antagonist has recently been developed to obtain a selective receptor inhibition reducing side effects like hyperkalemia and thereby making the drugs suitable for administration to CKD patients. Moreover, two new potassium-lowering therapies have shown to improve tolerance, allowing for higher dosage of renin-angiotensin system inhibitors and therefore enhancing their nephroprotective effect. Regardless of its cause, CKD is characterized by reduced renal regeneration capacity, microvascular damage, oxidative stress and inflammation, resulting in fibrosis and progressive, and irreversible nephron loss. Therefore, a holistic approach should be taken targeting the diverse processes and biological contexts that are associated with CKD progression. To date, therapeutic interventions when tubulointerstitial fibrosis is already established have proved to be insufficient, thus research effort should focus on unraveling early disease mechanisms. An array of novel therapeutic approaches targeting epigenetic regulators are now undergoing phase II or phase III trials and might provide a simultaneous regulatory activity that coordinately regulate different aspects of CKD progression.

Project description:Palmitoylation, a vital post-translational modification of proteins, has remained largely unexplored in immune-associated kidney diseases. This study is the first to reveal that palmitoylation plays a pivotal role in IgA nephropathy (IgAN) by regulating the activity of the transcription factor TEA Domain Transcription Factor 4 (TEAD4), thereby driving Th17 cell recruitment. Moreover, our findings suggest that inhibiting palmitoylation could act as a "braking" mechanism to slow disease progression. By analyzing clinical samples from IgAN patients and mouse models, we observed a significant positive correlation between the extent of Th17 cell infiltration in renal tissues and disease severity. Mechanistic investigations demonstrated that, under an inflammatory microenvironment, damaged renal tubular epithelial cells upregulate the expression of the chemokine CCL20 via TEAD4, thereby promoting Th17 cell recruitment. Notably, we identified that TEAD4 activity is regulated by its palmitoylation status, rather than changes in its protein expression levels. Further analysis identified zinc finger DHHC-type palmitoyltransferase 14 (ZDHHC14) as the critical enzyme mediating TEAD4 palmitoylation. ZDHHC14 was found to be highly expressed in the renal tissues of both IgAN patients and mouse models. Knockdown of ZDHHC14 significantly reduced CCL20 expression and diminished Th17 cell infiltration. In vivo therapeutic experiments confirmed that the ZDHHC inhibitor 2-bromopalmitate (2-BP) effectively alleviated Th17 cell infiltration and renal interstitial fibrosis, substantially delaying disease progression in IgAN mice. This study provides the first comprehensive insight into the regulatory mechanism of TEAD4 palmitoylation in IgAN progression. It further proposes a novel therapeutic approach targeting palmitoylation to modulate Th17 cell recruitment, offering critical theoretical foundations and potential clinical applications for the precise treatment of immune-mediated kidney diseases.

Dataset Information

TP53RK Drives the Progression of Chronic Kidney Disease by Phosphorylating Birc5.

Publications

TP53RK Drives the Progression of Chronic Kidney Disease by Phosphorylating Birc5.

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