bims-raghud 2024-11-03 papers

bims-raghud

Biomed News

on RagGTPases in human diseases

Issue of 2024‒11‒03
eight papers selected by
Irene Sambri, TIGEM

mTORC1 signaling and diabetic kidney disease.
An mTOR-Tfeb-Fabp7a signaling axis can be harnessed to ameliorate bag3 cardiomyopathy in adult zebrafish.
Cardiac rhabdomyoma: a rare feature of Birt-Hogg-Dubé syndrome.
TFEB agonist clomiphene citrate activates the autophagy-lysosomal pathway and ameliorates Alzheimer's disease symptoms in mice.
EZH2 inhibition or genetic ablation suppresses cyst growth in autosomal dominant polycystic kidney disease.
Placental-Heart Axis: An Evolutionary Perspective.
The Role of Natriuretic Peptides in the Management of Heart Failure with a Focus on the Patient with Diabetes.
Emerging role and function of Hippo-YAP/TAZ signaling pathway in musculoskeletal disorders.

Diabetol Int. 2024 Oct;15(4): 707-718

mTORC1 signaling and diabetic kidney disease.

Vinamra Swaroop, Eden Ozkan, Lydia Herrmann, Aaron Thurman, Olivia Kopasz-Gemmen, Abhiram Kunamneni, Ken Inoki.

  Diabetic kidney disease (DKD) represents the most lethal complication in both type 1 and type 2 diabetes. The disease progresses without obvious symptoms and is often refractory when apparent symptoms have emerged. Although the molecular mechanisms underlying the onset/progression of DKD have been extensively studied, only a few effective therapies are currently available. Pathogenesis of DKD involves multifaced events caused by diabetes, which include alterations of metabolisms, signals, and hemodynamics. While the considerable efficacy of sodium/glucose cotransporter-2 (SGLT2) inhibitors or angiotensin II receptor blockers (ARBs) for DKD has been recognized, the ever-increasing number of patients with diabetes and DKD warrants additional practical therapeutic approaches that prevent DKD from diabetes. One plausible but promising target is the mechanistic target of the rapamycin complex 1 (mTORC1) signaling pathway, which senses cellular nutrients to control various anabolic and catabolic processes. This review introduces the current understanding of the mTOR signaling pathway and its roles in the development of DKD and other chronic kidney diseases (CKDs), and discusses potential therapeutic approaches targeting this pathway for the future treatment of DKD.

Keywords:  Diabetic kidney disease (DKD); Diabetic nephropathy; Nutrients; Rapamycin; SGLT2 inhibitors; mTORC1

DOI:  https://doi.org/10.1007/s13340-024-00738-1
bioRxiv. 2024 Oct 27. pii: 2024.10.24.620101. [Epub ahead of print]

An mTOR-Tfeb-Fabp7a signaling axis can be harnessed to ameliorate bag3 cardiomyopathy in adult zebrafish.

Yonghe Ding, Feixiang Yan, Baul Yoon, Wei Wei, David Mondaca Ruff, Yuji Zhang, Xueying Lin, Xiaolei Xu.

Dysregulated proteostasis in cardiomyocytes is an important pathological event in BAG3 cardiomyopathy, which can be repaired by inhibiting mechanistic target of rapamycin (mTOR) for cardioprotective effects. Here, we aimed to uncover additional pathological events and therapeutic target genes via leveraging zebrafish genetics. We first assessed transcription factor EB ( tfeb ), a candidate gene that encodes a direct downstream phosphorylation target of mTOR signaling. We found that cardiomyocyte-specific transgenic overexpression of tfeb ( Tg[cmlc2:tfeb] ) is sufficient to repair defective proteostasis, attenuate accelerated cardiac senescence, a previously unrecognized phenotype in the bag3 cardiomyopathy model, and rescue cardiac dysfunction. Next, we compared cardiac transcriptomes between the Tg(cmlc2:tfeb) transgenic fish and the mtor xu015/+ mutant, and tested 4 commonly downregulated lipodystrophy genes using an F0-based genetic assay. We found that inhibition of the fatty acid binding protein a ( fabp7a ) gene, but not the other 3 genes, exerts therapeutic effects on bag3 cardiomyopathy. Conversely, fabp7a expression is elevated in bag3 cardiomyopathy model and cardiomyocyte-specific overexpression of fabp7a resulted in dysregulated proteostasis, accelerated cardiac senescence, as well as cardiac dysfunction. Together, these genetic studies in zebrafish uncovered Fabp7a activation and accelerated cardiac senescence as important pathological events in bag3 cardiomyopathy. The mTOR-Tfeb-Fabp7a signaling axis can be harnessed to repair these pathological changes and exert cardioprotective effects.

DOI: https://doi.org/10.1101/2024.10.24.620101
J Med Genet. 2024 Oct 26. pii: jmg-2024-110349. [Epub ahead of print]

Cardiac rhabdomyoma: a rare feature of Birt-Hogg-Dubé syndrome.

Florence Petit, Louise Devisme, Dimitri Tchernitchko, Olivia Domanski, Cecilia Gonzalez-Corcia, Lidwine Wemeau-Stervinou, Sophie Lejeune.

  Birt-Hogg-Dubé syndrome (BHDS) is a rare autosomal disorder, primarily characterised in adults by cutaneous features, pulmonary cysts that predispose to spontaneous pneumothorax and renal tumours. The syndrome is caused by pathogenic variants in the FLCN tumour suppressor gene, which plays a role in the mammalian target of rapamycin (mTOR) signalling pathway. We present the case of a newborn infant diagnosed with BHDS, who died of sudden cardiac death due to complications from cardiac rhabdomyoma. This is only the second reported case of such an association. Both cases were initially misdiagnosed with tuberous sclerosis complex, highlighting the diagnostic challenges. We discuss this differential diagnosis and suggest that cardiac rhabdomyomas, although rare, may be associated with BHDS and potentially life threatening. Therefore, we recommend cardiac screening in newborns at risk.

Keywords:  Cardiovascular Abnormalities; Disease Management; Genetic Variation; Heart Arrest

DOI:  https://doi.org/10.1136/jmg-2024-110349
J Biol Chem. 2024 Oct 23. pii: S0021-9258(24)02431-1. [Epub ahead of print] 107929

TFEB agonist clomiphene citrate activates the autophagy-lysosomal pathway and ameliorates Alzheimer's disease symptoms in mice.

Jieru Lin, Yi Yuan, Chunhuan Huang, Jiayu Zi, Lu Li, Jiamiao Liu, Xiaoting Wu, Wei Li, Qing Zhao, Yuyin Li, Zhenxing Liu, Aipo Diao.

  Autophagy is a conserved eukaryotic cellular clearance and recycling process through the lysosome-mediated degradation of damaged organelles and protein aggregates to maintain homeostasis. Impairment of the autophagy-lysosomal pathway is implicated in the pathogenesis of Alzheimer's disease (AD). Transcription factor EB (TFEB) is a master regulator of autophagy and lysosomal biogenesis. Therefore, activating TFEB and autophagy provides a novel strategy for AD treatment. We previously described that clomiphene citrate (CC) promotes nuclear translocation of TFEB and increases autophagy and lysosomal biogenesis. In this study, 7 and 3-month-old APP/PS1 mice were treated with TFEB agonist CC and assessed. The behavioral tests were performed using Morris water maze and open field test. Additional changes in Aβ pathology, autophagy and inflammatory response were determined. We found that CC activated TFEB and the autophagy-lysosomal pathway in neuronal cells. Moreover, using mouse model of Alzheimer's disease, CC treatment promoted clearance of Aβ plaques and ameliorated cognitive function in both 7 and 3-month-old APP/PS1 mice. The CC-induced activation of TFEB occurs by promoting acetylation of TFEB for nuclear translocation. These findings provide a molecular mechanism for the TFEB-mediated activation of the autophagy-lysosome pathway by CC, which has the potential to be repurposed and applied in the treatment or prevention of AD.

Keywords:  Alzheimer's disease; TFEB; autophagy; clomiphene citrate; lysosome

DOI:  https://doi.org/10.1016/j.jbc.2024.107929
J Transl Med. 2024 Oct 29. 22(1): 979

EZH2 inhibition or genetic ablation suppresses cyst growth in autosomal dominant polycystic kidney disease.

Jiayi Lv, Bingxue Lan, Lili Fu, Chaoran He, Wei Zhou, Xi Wang, Chenchen Zhou, Zhiguo Mao, Yupeng Chen, Changlin Mei, Cheng Xue.

  BACKGROUND: Autosomal Dominant Polycystic Kidney Disease (ADPKD) is a prevalent genetic disorder characterized by the formation of renal cysts leading to kidney failure. Despite known genetic underpinnings, the variability in disease progression suggests additional regulatory layers, including epigenetic modifications.METHODS: We utilized various ADPKD models, including Pkd1 and Ezh2 conditional knockout (Pkd1delta/delta:Ezh2delta/delta) mice, to explore the role of Enhancer of Zeste Homolog 2 (EZH2) in cystogenesis. Pharmacological inhibition of EZH2 was performed using GSK126 or EPZ-6438 across multiple models.
RESULTS: EZH2 expression was significantly upregulated in Pkd1-/- cells, Pkd1delta/delta mice, and human ADPKD kidneys. EZH2 inhibition attenuates cyst development in MDCK cells and a mouse embryonic kidney cyst model. Both Ezh2 conditional knockout and GSK126 treatment suppressed renal cyst growth and protected renal function in Pkd1delta/delta mice. Mechanistically, cAMP/PKA/CREB pathway increased EZH2 expression. EZH2 mediated cystogenesis by enhancing methylation and activation of STAT3, promoting cell cycle through p21 suppression, and stimulating non-phosphorylated β-catenin in Wnt signaling pathway. Additionally, EZH2 enhanced ferroptosis by inhibiting SLC7A11 and GPX4 in ADPKD.
CONCLUSION: Our findings elucidate the pivotal role of EZH2 in promoting renal cyst growth through epigenetic mechanisms and suggest that EZH2 inhibition or ablation may serve as a novel therapeutic approach for managing ADPKD.

Keywords:  Autosomal dominant; Enhancer of zeste homolog 2; Epigenetics; Ferroptosis; Polycystic kidney disease; p21

DOI:  https://doi.org/10.1186/s12967-024-05785-5
Int J Mol Sci. 2024 Oct 18. pii: 11212. [Epub ahead of print]25(20):

Placental-Heart Axis: An Evolutionary Perspective.

Jadyn Matthews, Brammy Rajakumar, Chrystalle Katte Carreon, Sarah U Morton.

  To maintain its development, the growing fetus is directly dependent on the placenta, an organ that acts as both a modulator and mediator. As an essential component of pregnancy that is derived from both maternal and fetal tissues, the placenta facilitates the passage of all oxygen and nutrients from the expecting parent to their fetuses. Further, the placenta conveys multiple impacts of the maternal environment to the growing fetus. The timing of placental development parallels that of the fetal cardiovascular system, and placental anomalies are implicated as a potential cause of congenital heart disease. For example, congenital heart disease is more common in pregnancies complicated by maternal preeclampsia, a condition characterized by placental dysfunction. Given the placenta's intermediary links to the maternal environment and fetal health outcomes, it is an emerging focus of evolutionary medicine, which seeks to understand how interactions between humans and the environment affect our biology and give rise to disease. The present review provides an overview of the evolutionary and developmental courses of the placenta as well as their implications on infant health.

Keywords:  congenital heart disease; evolutionary biology; placenta

DOI:  https://doi.org/10.3390/ijms252011212
J Clin Med. 2024 Oct 18. pii: 6225. [Epub ahead of print]13(20):

The Role of Natriuretic Peptides in the Management of Heart Failure with a Focus on the Patient with Diabetes.

Michela Vergani, Rosa Cannistraci, Gianluca Perseghin, Stefano Ciardullo.

  Natriuretic peptides (NPs) are polypeptide hormones involved in the homeostasis of the cardiovascular system. They are produced by cardiomyocytes and regulate circulating blood volume and sodium concentration. Clinically, measurements of brain natriuretic peptide (BNP) and N-terminal pro-BNP (NT-proBNP) are recommended by international guidelines as evidence is accumulating on their usefulness. They have a high negative predictive value, and in the setting of low NPs, a diagnosis of heart failure (HF) can be safely excluded in both emergency (BNP < 100 pg/mL, NT-proBNP < 300 pg/mL) and outpatient settings (BNP < 35 pg/mL and NT-proBNP < 125 pg/mL). Moreover, the 2023 consensus from the European Society of Cardiology suggests threshold values for inclusion diagnosis. These values are also associated with increased risks of major cardiovascular events, cardiovascular mortality, and all-cause mortality whether measured in inpatient or outpatient settings. Among patients without known HF, but at high risk of developing it (e.g., in the setting of diabetes mellitus, hypertension, or atherosclerotic cardiovascular disease), NPs may be useful in stratifying cardiovascular risk, optimizing therapy, and reducing the risk of developing overt HF. In the diabetes setting, risk stratification with the use of these peptides can guide the physician to a more informed and appropriate therapeutic choice as recommended by guidelines. Notably, NP levels should be carefully interpreted in light of certain conditions that may affect their reliability, such as chronic kidney disease and obesity, as well as demographic variables, including age and sex. In conclusion, NPs are useful in the diagnosis and prognosis of HF, but they also offer advantages in the primary prevention setting.

Keywords:  BNP; NT-proBNP; diabetes mellitus; heart failure; natriuretic peptide

DOI:  https://doi.org/10.3390/jcm13206225
Stem Cell Res Ther. 2024 Oct 29. 15(1): 386

Emerging role and function of Hippo-YAP/TAZ signaling pathway in musculoskeletal disorders.

Juanjuan Han, Jiale Zhang, Xiaoyi Zhang, Wenxin Luo, Lifei Liu, Yuqing Zhu, Qingfeng Liu, Xin-An Zhang.

  Hippo pathway is an evolutionarily conservative key pathway that regulates organ size and tissue regeneration by regulating cell proliferation, differentiation and apoptosis. Yes-associated protein 1 (YAP)/ WW domain-containing transcription regulator 1 (TAZ) serves as a pivotal transcription factor within the Hippo signaling pathway, which undergoes negative regulation by the Hippo pathway. The expression of YAP/TAZ affects various biological processes, including differentiation of osteoblasts (OB) and osteoclasts (OC), cartilage homeostasis, skeletal muscle development, regeneration and quality maintenance. At the same time, the dysregulation of the Hippo pathway can concurrently contribute to the development of various musculoskeletal disorders, including bone tumors, osteoporosis (OP), osteoarthritis (OA), intervertebral disc degeneration (IDD), muscular dystrophy, and rhabdomyosarcoma (RMS). Therefore, targeting the Hippo pathway has emerged as a promising therapeutic strategy for the treatment of musculoskeletal disorders. The focus of this review is to elucidate the mechanisms by which the Hippo pathway maintains homeostasis in bone, cartilage, and skeletal muscle, while also providing a comprehensive summary of the pivotal role played by core components of this pathway in musculoskeletal diseases. The efficacy and feasibility of Hippo pathway-related drugs for targeted therapy of musculoskeletal diseases are also discussed in our study. These endeavors offer novel insights into the application of Hippo signaling in musculoskeletal disorders, providing effective therapeutic targets and potential drug candidates for treating such conditions.

Keywords:  Cartilage; Hippo; Musculoskeletal diseases; Osteoblast; Osteoclast; Skeletal muscle; YAP/TAZ

DOI:  https://doi.org/10.1186/s13287-024-04011-9