bims-raghud Biomed News
on RagGTPases in human diseases
Issue of 2024–06–30
nine papers selected by
Irene Sambri, TIGEM
  1. Cardiac-Specific Suppression of Valosin-Containing Protein Induces Progressive Heart Failure and Premature Mortality Correlating with Temporal Dysregulations in mTOR Complex 2 and Protein Phosphatase 1.
  2. The role of mitochondrial dysfunction in kidney injury and disease.
  3. The endocrine basis of the cardio-renal axis: New perspectives regarding corin.
  4. Progress and breakthroughs in human kidney organoid research.
  5. Mitochondrial metabolic reprogramming in diabetic kidney disease.
  6. Kidney Aging and Chronic Kidney Disease.
  7. Modeling mTORopathy-related epilepsy in cultured murine hippocampal neurons using the multi-electrode array.
  8. Pivotal Role of mTOR in Non-Skin Manifestations of Psoriasis.
  9. Is There a Role for SGLT2 Inhibitors in Patients with End-Stage Kidney Disease?
  1. Int J Mol Sci. 2024 Jun 11. pii: 6445. [Epub ahead of print]25(12):
    Cardiac-Specific Suppression of Valosin-Containing Protein Induces Progressive Heart Failure and Premature Mortality Correlating with Temporal Dysregulations in mTOR Complex 2 and Protein Phosphatase 1.
    Xiaonan Sun, Xicong Tang, Hongyu Qiu.
      Valosin-containing protein (VCP), an ATPase-associated protein, is emerging as a crucial regulator in cardiac pathologies. However, the pivotal role of VCP in the heart under physiological conditions remains undetermined. In this study, we tested a hypothesis that sufficient VCP expression is required for cardiac development and physiological cardiac function. Thus, we generated a cardiac-specific VCP knockout (KO) mouse model and assessed the consequences of VCP suppression on the heart through physiological and molecular studies at baseline. Our results reveal that homozygous KO mice are embryonically lethal, whereas heterozygous KO mice with a reduction in VCP by ~40% in the heart are viable at birth but progressively develop heart failure and succumb to mortality at the age of 10 to 12 months. The suppression of VCP induced a selective activation of the mammalian target of rapamycin complex 1 (mTORC1) but not mTORC2 at the early age of 12 weeks. The prolonged suppression of VCP increased the expression (by ~2 folds) and nuclear translocation (by >4 folds) of protein phosphatase 1 (PP1), a key mediator of protein dephosphorylation, accompanied by a remarked reduction (~80%) in AKTSer473 phosphorylation in VCP KO mouse hearts at a later age but not the early stage. These temporal molecular alterations were highly associated with the progressive decline in cardiac function. Overall, our findings shed light on the essential role of VCP in the heart under physiological conditions, providing new insights into molecular mechanisms in the development of heart failure.
    Keywords:  heart failure; mTOR complex; protein phosphatase 1; valosin-containing protein
    DOI:  https://doi.org/10.3390/ijms25126445
  2. Autoimmun Rev. 2024 Jun 21. pii: S1568-9972(24)00067-3. [Epub ahead of print]23(6): 103576
    The role of mitochondrial dysfunction in kidney injury and disease.
    Xueqian Jia, Lifu Zhu, Qixing Zhu, Jiaxiang Zhang.
      Mitochondria are the main sites of aerobic respiration in the cell and mainly provide energy for the organism, and play key roles in adenosine triphosphate (ATP) synthesis, metabolic regulation, and cell differentiation and death. Mitochondrial dysfunction has been identified as a contributing factor to a variety of diseases. The kidney is rich in mitochondria to meet energy needs, and stable mitochondrial structure and function are essential for normal kidney function. Recently, many studies have shown a link between mitochondrial dysfunction and kidney disease, maintaining mitochondrial homeostasis has become an important target for kidney therapy. In this review, we integrate the role of mitochondrial dysfunction in different kidney diseases, and specifically elaborate the mechanism of mitochondrial reactive oxygen species (mtROS), autophagy and ferroptosis involved in the occurrence and development of kidney diseases, providing insights for improved treatment of kidney diseases.
    Keywords:  Dysfunction; Kidney injury; Mitochondria
    DOI:  https://doi.org/10.1016/j.autrev.2024.103576
  3. Physiol Rep. 2024 Jul;12(13): e16105
    The endocrine basis of the cardio-renal axis: New perspectives regarding corin.
    Zaid Abassi, Dalit B Hamo-Giladi, Safa Kinaneh, Samuel N Heyman.
      The central role of natriuretic peptides (NPs) in the complex cardio-renal integrated physiology and organ failure has been revealed over the last four decades. Atrial natriuretic peptide (ANP), the oldest representative of the NPs family, is produced through conversion of proANP to the mature peptide by corin, a trans-membrane protease localized to the cardiac myocyte membrane. Similarly, brain natriuretic peptide (BNP) is generated by furin, which cleaves proBNP to BNP in myocytes. Though the components of NPs system, their synthesis and target organs are well established, understanding their role in the interplay between the heart and the kidney is steadily evolving. In this context, Feldman et al. (New England Journal of Medicine, 389, 1685) recently described patients with hypertension, cardiomyopathy, atrial arrhythmia and left atrial fibrosis, associated with a homozygous loss-of-function variant of the gene encoding corin (Cor-/-). Notably, reduced baseline urinary electrolyte and creatinine excretion have been observed in one of the studied patients. This renal excretory functional impairment could be attributed to the lack of cardiac-derived ANP in these patients, as implied by Feldman et al. Yet, in this mini-review we suggest that this aberrant renal manifestation may principally stem from lack of local ANP production at renal tissue, as corin is normally expressed in proximal tubules, Henle's loop and collecting ducts, with locally produced ANP provoking Na+ and water exertion. Collectively, it seems that beside the classic well-established cardio-renal axis, the renal NPs system functions as local endocrine machinery in the regulation of sodium excretion.
    Keywords:  cardiorenal axis; corin; edema; natriuresis; natriuretic peptides
    DOI:  https://doi.org/10.14814/phy2.16105
  4. Biochem Biophys Rep. 2024 Sep;39 101736
    Progress and breakthroughs in human kidney organoid research.
    Qi Liu, Liang Yue, Jiu Deng, Yingxia Tan, Chengjun Wu.
      The three-dimensional (3D) kidney organoid is a breakthrough model for recapitulating renal morphology and function in vitro, which is grown from stem cells and resembles mammalian kidney organogenesis. Currently, protocols for cultivating this model from induced pluripotent stem cells (iPSCs) and patient-derived adult stem cells (ASCs) have been widely reported. In recent years, scientists have focused on combining cutting-edge bioengineering and bioinformatics technologies to improve the developmental accuracy of kidney organoids and achieve high-throughput experimentation. As a remarkable tool for mechanistic research of the renal system, kidney organoid has both potential and challenges. In this review, we have described the evolution of kidney organoid establishment methods and highlighted the latest progress leading to a more sophisticated kidney transformation research model. Finally, we have summarized the main applications of renal organoids in exploring kidney disease.
    Keywords:  Diseases; Kidney; Nephron; Organoid; Stem cell
    DOI:  https://doi.org/10.1016/j.bbrep.2024.101736
  5. Cell Death Dis. 2024 Jun 24. 15(6): 442
    Mitochondrial metabolic reprogramming in diabetic kidney disease.
    Xiaoting Fan, Meilin Yang, Yating Lang, Shangwei Lu, Zhijuan Kong, Ying Gao, Ning Shen, Dongdong Zhang, Zhimei Lv.
      Diabetic kidney disease, known as a glomerular disease, arises from a metabolic disorder impairing renal cell function. Mitochondria, crucial organelles, play a key role in substance metabolism via oxidative phosphorylation to generate ATP. Cells undergo metabolic reprogramming as a compensatory mechanism to fulfill energy needs for survival and growth, attracting scholarly attention in recent years. Studies indicate that mitochondrial metabolic reprogramming significantly influences the pathophysiological progression of DKD. Alterations in kidney metabolism lead to abnormal expression of signaling molecules and activation of pathways, inducing oxidative stress-related cellular damage, inflammatory responses, apoptosis, and autophagy irregularities, culminating in renal fibrosis and insufficiency. This review delves into the impact of mitochondrial metabolic reprogramming on DKD pathogenesis, emphasizing the regulation of metabolic regulators and downstream signaling pathways. Therapeutic interventions targeting renal metabolic reprogramming can potentially delay DKD progression. The findings underscore the importance of focusing on metabolic reprogramming to develop safer and more effective therapeutic approaches.
    DOI:  https://doi.org/10.1038/s41419-024-06833-0
  6. Int J Mol Sci. 2024 Jun 14. pii: 6585. [Epub ahead of print]25(12):
    Kidney Aging and Chronic Kidney Disease.
    Yingying Zhang, Chen Yu, Xiaogang Li.
      The process of aging inevitably leads to an increase in age-related comorbidities, including chronic kidney disease (CKD). In many aspects, CKD can be considered a state of accelerated and premature aging. Aging kidney and CKD have numerous common characteristic features, ranging from pathological presentation and clinical manifestation to underlying mechanisms. The shared mechanisms underlying the process of kidney aging and the development of CKD include the increase in cellular senescence, the decrease in autophagy, mitochondrial dysfunction, and the alterations of epigenetic regulation, suggesting the existence of potential therapeutic targets that are applicable to both conditions. In this review, we provide a comprehensive overview of the common characteristics between aging kidney and CKD, encompassing morphological changes, functional alterations, and recent advancements in understanding the underlying mechanisms. Moreover, we discuss potential therapeutic strategies for targeting senescent cells in both the aging process and CKD.
    Keywords:  cell senescence; chronic kidney disease; kidney aging
    DOI:  https://doi.org/10.3390/ijms25126585
  7. Exp Neurol. 2024 Jun 22. pii: S0014-4886(24)00200-0. [Epub ahead of print] 114874
    Modeling mTORopathy-related epilepsy in cultured murine hippocampal neurons using the multi-electrode array.
    Anouk M Heuvelmans, Martina Proietti Onori, Monica Frega, Jeffrey D de Hoogen, Eveline Nel, Ype Elgersma, Geeske M van Woerden.
      The mechanistic target of rapamycin complex 1 (mTORC1) signaling pathway is a ubiquitous cellular pathway. mTORopathies, a group of disorders characterized by hyperactivity of the mTORC1 pathway, illustrate the prominent role of the mTOR pathway in disease pathology, often profoundly affecting the central nervous system. One of the most debilitating symptoms of mTORopathies is drug-resistant epilepsy, emphasizing the urgent need for a deeper understanding of disease mechanisms to develop novel anti-epileptic drugs. In this study, we explored the multiwell Multi-electrode array (MEA) system as a tool to identify robust network activity parameters in an approach to model mTORopathy-related epilepsy in vitro. To this extent, we cultured mouse primary hippocampal neurons on the multiwell MEA to identify robust network activity phenotypes in mTORC1-hyperactive neuronal networks. mTOR-hyperactivity was induced either through deletion of Tsc1 or overexpression of a constitutively active RHEB variant identified in patients, RHEBp.P37L. mTORC1 dependency of the phenotypes was assessed using rapamycin, and vigabatrin was applied to treat epilepsy-like phenotypes. We show that hyperactivity of the mTORC1 pathway leads to aberrant network activity. In both the Tsc1-KO and RHEB-p.P37L models, we identified changes in network synchronicity, rhythmicity, and burst characteristics. The presence of these phenotypes is prevented upon early treatment with the mTORC1-inhibitor rapamycin. Application of rapamycin in mature neuronal cultures could only partially rescue the network activity phenotypes. Additionally, treatment with the anti-epileptic drug vigabatrin reduced network activity and restored burst characteristics. Taken together, we showed that mTORC1-hyperactive neuronal cultures on the multiwell MEA system present reliable network activity phenotypes that can be used as an assay to explore the potency of new drug treatments targeting epilepsy in mTORopathy patients and may give more insights into the pathophysiological mechanisms underlying epilepsy in these patients.
    Keywords:  Epilepsy; Multi-electrode array; Network activity; Primary hippocampal neurons; Rapamycin; Vigabatrin; mTORopathy
    DOI:  https://doi.org/10.1016/j.expneurol.2024.114874
  8. Int J Mol Sci. 2024 Jun 20. pii: 6778. [Epub ahead of print]25(12):
    Pivotal Role of mTOR in Non-Skin Manifestations of Psoriasis.
    Ka Joo, Claudio Karsulovic, Milisa Sore, Lia Hojman.
      Psoriasis is a chronic inflammatory condition affecting 2% of the Western population. It includes diverse manifestations influenced by genetic predisposition, environmental factors, and immune status. The sustained activation of mTOR is a key element in psoriasis pathogenesis, leading to an uncontrolled proliferation of cytokines. Furthermore, mTOR activation has been linked with the transition from psoriasis to non-skin manifestations such as psoriatic arthritis and cardiovascular events. While therapies targeting pro-inflammatory cytokines have shown efficacy, additional pathways may offer therapeutic potential. The PI3K/Akt/mTOR pathway, known for its role in cell growth, proliferation, and metabolism, has emerged as a potential therapeutic target in psoriasis. This review explores the relevance of mTOR in psoriasis pathophysiology, focusing on its involvement in cutaneous and atheromatous plaque proliferation, psoriatic arthritis, and cardiovascular disease. The activation of mTOR promotes keratinocyte and synovial cell proliferation, contributing to plaque formation and joint inflammation. Moreover, mTOR activation may exacerbate the cardiovascular risk by promoting pro-inflammatory cytokine production and dysregulation lipid and glucose metabolism. The inhibition of mTOR has shown promise in preclinical studies, reducing skin inflammation and plaque proliferation. Furthermore, mTOR inhibition may mitigate cardiovascular risk by modulating cholesterol metabolism and attenuating atherosclerosis progression. Understanding the role of mTOR in psoriasis, psoriatic arthritis, and cardiovascular disease provides insight into the potential treatment avenues and sheds light on the complex interplay of the immune and metabolic pathways in these conditions.
    Keywords:  cardiovascular disease; mTOR pathway; psoriasis
    DOI:  https://doi.org/10.3390/ijms25126778
  9. Curr Hypertens Rep. 2024 Jun 24.
    Is There a Role for SGLT2 Inhibitors in Patients with End-Stage Kidney Disease?
    Rehma Siddiqui, Yoshitsugu Obi, Neville R Dossabhoy, Tariq Shafi.
       PURPOSE OF REVIEW: Chronic kidney disease and end-stage kidney disease (ESKD) are well-established risk factors for cardiovascular disease (CVD), the leading cause of mortality in the dialysis population. Conventional therapies, such as statins, blood pressure control, and renin-angiotensin-aldosterone system blockade, have inadequately addressed this cardiovascular risk, highlighting the unmet need for effective treatment strategies. Sodium-glucose transporter 2 (SGLT2) inhibitors have demonstrated significant renal and cardiovascular benefits among patients with type 2 diabetes, heart failure, or CKD at risk of progression. Unfortunately, efficacy data in dialysis patients is lacking as ESKD was an exclusion criterion for all major clinical trials of SGLT2 inhibitors. This review explores the potential of SGLT2 inhibitors in improving cardiovascular outcomes among patients with ESKD, focusing on their direct cardiac effects.
    RECENT FINDINGS: Recent clinical and preclinical studies have shown promising data for the application of SGLT2 inhibitors to the dialysis population. SGLT2 inhibitors may provide cardiovascular benefits to dialysis patients, not only indirectly by preserving the remaining kidney function and improving anemia but also directly by lowering intracellular sodium and calcium levels, reducing inflammation, regulating autophagy, and alleviating oxidative stress and endoplasmic reticulum stress within cardiomyocytes and endothelial cells. This review examines the current clinical evidence and experimental data supporting the use of SGLT2 inhibitors, discusses its potential safety concerns, and outlines ongoing clinical trials in the dialysis population. Further research is needed to evaluate the safety and effectiveness of SGLT2 inhibitor use among patients with ESKD.
    Keywords:  Autophagy; Chronic kidney disease; Dialysis; End-stage kidney disease; Heart failure; Inflammation; Mortality; Oxydative stress; Residual kidney function; Sodium-glucose cotransporter-2 inhibitors
    DOI:  https://doi.org/10.1007/s11906-024-01314-3
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