Fasudil compensates podocyte injury via CaMK4/Rho GTPases signal and actin cytoskeleton-dependent activation of YAP in MRL/lpr mice

Tian, Fengyuan; Huang, Shuo; Xu, Wangda; Xie, Guangyong; Gan, Yihong; Huang, Fugang; Fan, Yongsheng; Bao, Jie

doi:10.1016/j.intimp.2023.110199

Cited by 7 publications

(4 citation statements)

References 49 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The RhoA/ROCK pathway is implicated in the pathogenesis of various kidney diseases, including diabetic kidney disease, acute kidney injury ( Komers, 2013 ; Wang et al, 2018 ), and LN-associated kidney injury. Fengyuan Tian et al demonstrated that Fasudil, a Rho family small GTP-binding protein (Rho GTPase) inhibitor, can reduce podocyte damage in LN by interfering with upstream CaMK4/Rho GTPase signaling pathway in podocytes in lupus-prone mice ( Tian et al, 2023 ). A recent study demonstrated that tacrolimus can cause Ang II-induced vasoconstriction through the activation of the RhoA/ROCK pathway ( Wang et al, 2022 ).…”

Section: Non-immune Mechanismmentioning

confidence: 99%

Mechanism of tacrolimus in the treatment of lupus nephritis

Wang,

Zhou,

Niu

et al. 2024

Front. Pharmacol.

View full text Add to dashboard Cite

Systemic lupus erythematosus (SLE) is a complex autoimmune disorder, with more than half of the patients developing lupus nephritis (LN), which significantly contributes to chronic kidney disease (CKD) and end-stage renal disease (ESRD). The treatment of lupus nephritis has always been challenging. Tacrolimus (TAC), an effective immunosuppressant, has been increasingly used in the treatment of LN in recent years. This review aims to explore the mechanisms of action of tacrolimus in treating LN. Firstly, we briefly introduce the pharmacological properties of tacrolimus, including its role as a calcineurin (CaN) inhibitor, exerting immunosuppressive effects by inhibiting T cell activation and cytokine production. Subsequently, we focus on various other immunomodulatory mechanisms of tacrolimus in LN therapy, including its effects on T cells, B cells, and immune cells in kidney. Particularly, we emphasize tacrolimus’ regulatory effect on inflammatory mediators and its importance in modulating the Th1/Th2 and Th17/Treg balance. Additionally, we review its effects on actin cytoskeleton, angiotensin II (Ang II)-specific vascular contraction, and P-glycoprotein activity, summarizing its impacts on non-immune mechanisms. Finally, we summarize the efficacy and safety of tacrolimus in clinical studies and trials. Although some studies have shown significant efficacy of tacrolimus in treating LN, its safety remains a challenge. We outline the potential adverse reactions of long-term tacrolimus use and provide suggestions on effectively monitoring and managing these adverse reactions in clinical practice. In general, tacrolimus, as a novel immunosuppressant, holds promising prospects for treating LN. Of course, further research is needed to better understand its therapeutic mechanisms and ensure its safety and efficacy in clinical practice.

show abstract

Section: Non-immune Mechanismmentioning

confidence: 99%

Mechanism of tacrolimus in the treatment of lupus nephritis

Wang,

Zhou,

Niu

et al. 2024

Front. Pharmacol.

View full text Add to dashboard Cite

show abstract

“…It attenuated angiotensin II (Ang II)-induced cytoskeleton rearrangement and preserved podocyte mobility by modulating SD proteins, including nephrin and CD2AP [ 200 ]. Tian and colleagues recently clarified that in MRL/lpr mice (an animal model of LN), Fasudil sustained podocyte actin cytoskeleton by inhibiting CaMK4/RhoA signaling and inducing the release of YAP from the 14-3-3β (a chaperonin protein for YAP) to make up for the podocyte damage [ 201 ]. Another Rho kinase inhibitor, Y27632, notably attenuated podocyte actin cytoskeleton rearrangement in Ang II-treated rats [ 202 ].…”

Section: Therapeutic Implicationsmentioning

confidence: 99%

Cytoskeleton Rearrangement in Podocytopathies: An Update

Ma,

Qiu,

Zhang

2024

IJMS

View full text Add to dashboard Cite

Podocyte injury can disrupt the glomerular filtration barrier (GFB), leading to podocytopathies that emphasize podocytes as the glomerulus’s key organizer. The coordinated cytoskeleton is essential for supporting the elegant structure and complete functions of podocytes. Therefore, cytoskeleton rearrangement is closely related to the pathogenesis of podocytopathies. In podocytopathies, the rearrangement of the cytoskeleton refers to significant alterations in a string of slit diaphragm (SD) and focal adhesion proteins such as the signaling node nephrin, calcium influx via transient receptor potential channel 6 (TRPC6), and regulation of the Rho family, eventually leading to the disorganization of the original cytoskeletal architecture. Thus, it is imperative to focus on these proteins and signaling pathways to probe the cytoskeleton rearrangement in podocytopathies. In this review, we describe podocytopathies and the podocyte cytoskeleton, then discuss the molecular mechanisms involved in cytoskeleton rearrangement in podocytopathies and summarize the effects of currently existing drugs on regulating the podocyte cytoskeleton.

show abstract

“…Fasudil is the only clinically approved Rho GTPase inhibitor, and in MRL/lpr mice, Fasudil significantly reduces proteinuria by inhibiting Ca 2+ /calmodulin-dependent kinase (CaMK)4/RhoA signaling and preventing Rho GTPase-dependent cytoskeletal fragmentation, thereby preserving podocyte actin structure and foot process morphology. 103 Tacrolimus, a calcineurin inhibitor commonly used in LN clinical practice, has urinary protein-reducing and renal protective effects that can be partially attributed to its role in stabilizing the actin skeleton and preserving podocytes numbers. 104 These findings highlight the benefits of maintaining podocyte cytoskeleton stability in future LN therapies.…”

Section: Targeting Podocyte Structurementioning

confidence: 99%

“…Small guanosine triphosphate hydrolases from the Rho family are essential in sustaining the podocyte cytoskeleton. Fasudil is the only clinically approved Rho GTPase inhibitor, and in MRL/lpr mice, Fasudil significantly reduces proteinuria by inhibiting Ca 2+ /calmodulin‐dependent kinase (CaMK)4/RhoA signaling and preventing Rho GTPase‐dependent cytoskeletal fragmentation, thereby preserving podocyte actin structure and foot process morphology 103 …”

Section: Podocyte‐targeted Therapies In Lnmentioning

confidence: 99%

Podocyte injury and death: New insights into lupus nephritis pathogenesis and therapy

Shi,

Wang,

Tang

et al. 2023

Rheumatology & Autoimmunity

View full text Add to dashboard Cite

Lupus nephritis (LN), an immune complex‐mediated glomerulonephritis, is one of the most severe complications of systemic lupus erythematosus. Current therapeutic regimens for LN mainly involve nonspecific immunosuppressants and biologics targeting immune cells, but these treatments are not always effective and some patients are nonresponsive and susceptible to recurrence. Podocytes are essential for maintaining the glomerular filtration barrier. Injury to and loss of podocytes lead to proteinuria, a hallmark of renal involvement and LN. Podocytes are, therefore, emerging as prospective therapeutic targets for LN. There are numerous mechanisms underlying podocyte malfunction in LN, with autophagy, mitochondrial dysregulation, and programmed cell death being the main processes behind podocyte loss. This review summarizes recent advances in understanding podocyte dysfunction in LN pathogenesis and discusses potential therapeutic interventions targeting podocytes in LN.

show abstract

Fasudil compensates podocyte injury via CaMK4/Rho GTPases signal and actin cytoskeleton-dependent activation of YAP in MRL/lpr mice

Cited by 7 publications

References 49 publications

Mechanism of tacrolimus in the treatment of lupus nephritis

Mechanism of tacrolimus in the treatment of lupus nephritis

Cytoskeleton Rearrangement in Podocytopathies: An Update

Podocyte injury and death: New insights into lupus nephritis pathogenesis and therapy

Contact Info

Product

Resources

About