bims-raghud Biomed News
on RagGTPases in human diseases
Issue of 2024–04–28
eleven papers selected by
Irene Sambri, TIGEM
  1. Kidney collecting duct cell type composition is regulated by Notch signaling via modulation of mTORC1.
  2. Advances in the Pathogenesis of Diabetic Kidney Disease.
  3. Renal antiporter ClC-5 regulates collagen I/IV through the β-catenin pathway and lysosomal degradation.
  4. Targeting ferroptosis for treating kidney disease.
  5. Regeneration of Nonhuman Primate Hearts With Human Induced Pluripotent Stem Cell-Derived Cardiac Spheroids.
  6. Carboxymethylated Desmodium styracifolium polysaccharide reduces the risk of calcium oxalate kidney stone formation by inhibiting crystal adhesion and promoting crystal endocytosis.
  7. Female protection against diabetic kidney disease is regulated by kidney-specific AMPK activity.
  8. Targeting ferroptosis as a prospective therapeutic approach for diabetic nephropathy.
  9. Mitochondrial Kinase Signaling for Cardioprotection.
  10. Hepato-Cardio-Renal Syndrome.
  11. Dimorphic effect of TFE3 in determining mitochondrial and lysosomal content in muscle following denervation.
  1. bioRxiv. 2024 Apr 09. pii: 2024.04.09.587573. [Epub ahead of print]
    Kidney collecting duct cell type composition is regulated by Notch signaling via modulation of mTORC1.
    Jennifer deRiso, Malini Mukherjee, Madhusudhana Janga, Alicia Simmons, Michael Kareta, Jianning Tao, Indra Chandrasekar, Kameswaran Surendran.
      The plasticity and diversity of cell types with specialized functions likely defines the capacity of multicellular organisms to adapt to physiologic stressors. The kidney collecting ducts contribute to water, electrolyte, and pH homeostasis and are composed of mature intermingled epithelial cell types that are susceptible to transdifferentiate. The conversion of kidney collecting duct principal cells to intercalated cells is actively inhibited by Notch signaling to ensure urine concentrating capability. Here we identify Hes1, a target of Notch signaling, allows for maintenance of functionally distinct epithelial cell types within the same microenvironment by regulating mechanistic target of rapamycin complex 1 (mTORC1) activity. Hes1 directly represses the expression of insulin receptor substrate 1 ( Irs1 ), an upstream component of mTOR pathway and suppresses mTORC1 activity in principal cells. Genetic inactivation of tuberous sclerosis complex 2 ( Tsc2 ) to increase mTORC1 activity in mature principal cells is sufficient to promote acquisition of intercalated cell properties, while inhibition of mTORC1 in adult kidney epithelia suppresses intercalated cell properties. Considering that mTORC1 integrates environmental cues, the linkage of functionally distinct epithelial cell types to mTORC1 activity levels likely allows for cell plasticity to be regulated by physiologic and metabolic signals and the ability to sense/transduce these signals.
    DOI:  https://doi.org/10.1101/2024.04.09.587573
  2. Int J Mol Sci. 2024 Apr 22. pii: 4563. [Epub ahead of print]25(8):
    Advances in the Pathogenesis of Diabetic Kidney Disease.
    Christodoula Kourtidou, Konstantinos Tziomalos.
      Diabetic kidney disease (DKD) is both a frequent complication of diabetes mellitus (DM) [...].
    DOI:  https://doi.org/10.3390/ijms25084563
  3. Life Sci Alliance. 2024 Jul;pii: e202302444. [Epub ahead of print]7(7):
    Renal antiporter ClC-5 regulates collagen I/IV through the β-catenin pathway and lysosomal degradation.
    Mònica Durán, Gema Ariceta, Maria E Semidey, Carla Castells-Esteve, Andrea Casal-Pardo, Baisong Lu, Anna Meseguer, Gerard Cantero-Recasens.
      Mutations in Cl-/H+ antiporter ClC-5 cause Dent's disease type 1 (DD1), a rare tubulopathy that progresses to renal fibrosis and kidney failure. Here, we have used DD1 human cellular models and renal tissue from DD1 mice to unravel the role of ClC-5 in renal fibrosis. Our results in cell systems have shown that ClC-5 deletion causes an increase in collagen I (Col I) and IV (Col IV) intracellular levels by promoting their transcription through the β-catenin pathway and impairing their lysosomal-mediated degradation. Increased production of Col I/IV in ClC-5-depleted cells ends up in higher release to the extracellular medium, which may lead to renal fibrosis. Furthermore, our data have revealed that 3-mo-old mice lacking ClC-5 (Clcn5 +/- and Clcn5 -/- ) present higher renal collagen deposition and fibrosis than WT mice. Altogether, we describe a new regulatory mechanism for collagens' production and release by ClC-5, which is altered in DD1 and provides a better understanding of disease progression to renal fibrosis.
    DOI:  https://doi.org/10.26508/lsa.202302444
  4. Clin Exp Nephrol. 2024 Apr 22.
    Targeting ferroptosis for treating kidney disease.
    Eikan Mishima.
      Ferroptosis is a type of regulated cell death hallmarked by iron-mediated excessive lipid oxidation. Over the past decade since the coining of the term ferroptosis, advances in research have led to the identification of intracellular processes that regulate ferroptosis such as GSH-GPX4 pathway and FSP1-coenzyme Q10/vitamin K pathway. From a disease perspective, the involvement of ferroptosis in pathological conditions including kidney disease has attracted attention. In terms of renal pathophysiology, ferroptosis has been widely investigated for its involvement in ischemia-reperfusion injury, nephrotoxin-induced kidney damage and other renal diseases. Therefore, therapeutic interventions targeting ferroptosis are expected to become a new therapeutic approach for these diseases. However, when considering cell death as a therapeutic target, careful consideration must be given to (i) in which type of cells, (ii) which type of cell death mode, and (iii) in which stage or temporal window of the disease. In the next decade, elucidation of the true involvement of ferroptosis in kidney disease setting in human, and development of clinically applicable and effective therapeutic drugs that target ferroptosis are warranted.
    Keywords:  Cell death; Ischemia reperfusion injury; Lipid peroxidation; Lipid radicals; Oxidative stress; Warfarin
    DOI:  https://doi.org/10.1007/s10157-024-02491-w
  5. Circulation. 2024 Apr 26.
    Regeneration of Nonhuman Primate Hearts With Human Induced Pluripotent Stem Cell-Derived Cardiac Spheroids.
    Hideki Kobayashi, Shugo Tohyama, Hajime Ichimura, Noburo Ohashi, Shuji Chino, Yusuke Soma, Hidenori Tani, Yuki Tanaka, Xiao Yang, Naoko Shiba, Shin Kadota, Kotaro Haga, Taijun Moriwaki, Yuika Morita-Umei, Tomohiko C Umei, Otoya Sekine, Yoshikazu Kishino, Hideaki Kanazawa, Hiroyuki Kawagishi, Mitsuhiko Yamada, Kazumasa Narita, Takafumi Naito, Tatsuichiro Seto, Koichiro Kuwahara, Yuji Shiba, Keiichi Fukuda.
       BACKGROUND: The clinical application of human induced pluripotent stem cell-derived cardiomyocytes (CMs) for cardiac repair commenced with the epicardial delivery of engineered cardiac tissue; however, the feasibility of the direct delivery of human induced pluripotent stem cell-derived CMs into the cardiac muscle layer, which has reportedly induced electrical integration, is unclear because of concerns about poor engraftment of CMs and posttransplant arrhythmias. Thus, in this study, we prepared purified human induced pluripotent stem cell-derived cardiac spheroids (hiPSC-CSs) and investigated whether their direct injection could regenerate infarcted nonhuman primate hearts.
    METHODS: We performed 2 separate experiments to explore the appropriate number of human induced pluripotent stem cell-derived CMs. In the first experiment, 10 cynomolgus monkeys were subjected to myocardial infarction 2 weeks before transplantation and were designated as recipients of hiPSC-CSs containing 2×107 CMs or the vehicle. The animals were euthanized 12 weeks after transplantation for histological analysis, and cardiac function and arrhythmia were monitored during the observational period. In the second study, we repeated the equivalent transplantation study using more CMs (6×107 CMs).
    RESULTS: Recipients of hiPSC-CSs containing 2×107 CMs showed limited CM grafts and transient increases in fractional shortening compared with those of the vehicle (fractional shortening at 4 weeks after transplantation: 26.2±2.1%; 19.3±1.8%; P<0.05), with a low incidence of posttransplant arrhythmia. Transplantation of increased dose of CMs resulted in significantly greater engraftment and long-term contractile benefits (fractional shortening at 12 weeks after transplantation: 22.5±1.0%; 16.6±1.1%; P<0.01, left ventricular ejection fraction at 12 weeks after transplantation: 49.0±1.4%; 36.3±2.9%; P<0.01). The incidence of posttransplant arrhythmia slightly increased in recipients of hiPSC-CSs containing 6×107 CMs.
    CONCLUSIONS: We demonstrated that direct injection of hiPSC-CSs restores the contractile functions of injured primate hearts with an acceptable risk of posttransplant arrhythmia. Although the mechanism for the functional benefits is not fully elucidated, these findings provide a strong rationale for conducting clinical trials using the equivalent CM products.
    Keywords:  cardiac spheroids (CS); cardiomyocyte (CM); cynomolgus monkey; human induced pluripotent stem cell (hiPSC); myocardial infarction; posttransplant arrhythmia
    DOI:  https://doi.org/10.1161/CIRCULATIONAHA.123.064876
  6. J Cell Physiol. 2024 Apr 22.
    Carboxymethylated Desmodium styracifolium polysaccharide reduces the risk of calcium oxalate kidney stone formation by inhibiting crystal adhesion and promoting crystal endocytosis.
    Zhi Wang, Li Liu, Yao-Wang Zhao, Xin-Yi Tong, Gu-Hua Tang, Jian-Ming Ouyang.
      The inhibition of cell surface crystal adhesion and an appropriate increase in crystal endocytosis contribute to the inhibition of kidney stone formation. In this study, we investigated the effects of different degrees of carboxymethylation on these processes. An injury model was established by treating human renal proximal tubular epithelial (HK-2) cells with 98.3 ± 8.1 nm calcium oxalate dihydrate (nanoCOD) crystals. The HK-2 cells were protected with carboxy (-COOH) Desmodium styracifolium polysaccharides at 1.17% (DSP0), 7.45% (CDSP1), 12.2% (CDSP2), and 17.7% (CDSP3). Changes in biochemical indexes and effects on nanoCOD adhesion and endocytosis were detected. The protection of HK-2 cells from nanoCOD-induced oxidative damage by carboxymethylated Desmodium styracifolium polysaccharides (CDSPs) is closely related to the protection of subcellular organelles, such as mitochondria. CDSPs can reduce crystal adhesion on the cell surface and maintain appropriate crystal endocytosis, thereby reducing the risk of kidney stone formation. CDSP2 with moderate -COOH content showed the strongest protective activity among the CDSPs.
    Keywords:  calcium oxalate dihydrate; carboxymethylated polysaccharide; cell adhesion; crystal endocytosis; kidney stones
    DOI:  https://doi.org/10.1002/jcp.31272
  7. Diabetes. 2024 Apr 24. pii: db230807. [Epub ahead of print]
    Female protection against diabetic kidney disease is regulated by kidney-specific AMPK activity.
    Hak Joo Lee, Liang Min, Jingli Gao, Shane Matta, Viktor Drel, Afaf Saliba, Ian Tamayo, Richard Montellano, Leila Hejazi, Soumya Maity, Guogang Xu, Brian I Grajeda, Sourav Roy, Kenneth R Hallows, Goutam Ghosh Choudhury, Balakuntalam S Kasinath, Kumar Sharma.
      Reduced kidney AMPK activity is associated with nutrient stress-induced chronic kidney disease (CKD) in male mice. In contrast, female mice resist nutrient stress-induced CKD. The role of kidney AMPK in sex-related organ protection against nutrient stress and metabolite changes were evaluated in diabetic kidney tubule-specific AMPKγ2KO (KTAMPKγ2KO) male and female mice. In WT males, diabetes increased albuminuria, urinary kidney injury molecule-1, hypertension, kidney p70S6K phosphorylation, and kidney matrix accumulation; these features were not exacerbated with KTAMPKγ2KO. Whereas WT females had protection against diabetes induced kidney injury, KTAMPKγ2KO led to loss of female protection against kidney disease. 17β-estradiol ameliorated high glucose-induced AMPK inactivation, p70S6K phosphorylation and matrix protein accumulation in kidney tubule cells. The mechanism for female protection against diabetes-induced kidney injury is likely via an estrogen-AMPK pathway, as inhibition of AMPK led to loss of estrogen protection to glucose-induced mTORC1 activation and matrix production. RNA-seq and metabolomic analysis identified a decrease in the degradation pathway of phenylalanine and tyrosine resulting in increased urinary phenylalanine and tyrosine levels in females. The metabolite levels correlated with loss of female protection. The findings provide new insights to explain evolutionary advantages to females during states of nutrient challenges.
    DOI:  https://doi.org/10.2337/db23-0807
  8. Ann Med. 2024 Dec;56(1): 2346543
    Targeting ferroptosis as a prospective therapeutic approach for diabetic nephropathy.
    Qinrui Wu, Fengjuan Huang.
      Diabetic nephropathy (DN) is a severe complication of diabetes mellitus, causing a substantive threat to the public, which receives global concern. However, there are limited drugs targeting the treatment of DN. Owing to this, it is highly crucial to investigate the pathogenesis and potential therapeutic targets of DN. The process of ferroptosis is a type of regulated cell death (RCD) involving the presence of iron, distinct from autophagy, apoptosis, and pyroptosis. A primary mechanism of ferroptosis is associated with iron metabolism, lipid metabolism, and the accumulation of ROS. Recently, many studies testified to the significance of ferroptosis in kidney tissue under diabetic conditions and explored the drugs targeting ferroptosis in DN therapy. Our review summarized the most current studies between ferroptosis and DN, along with investigating the significant processes of ferroptosis in different kidney cells, providing a novel target treatment option for DN.
    Keywords:  Diabetic nephropathy; TEC; ferroptosis; glomerular endothelial cell; mesangial cell; podocyte
    DOI:  https://doi.org/10.1080/07853890.2024.2346543
  9. Int J Mol Sci. 2024 Apr 19. pii: 4491. [Epub ahead of print]25(8):
    Mitochondrial Kinase Signaling for Cardioprotection.
    Kerstin Boengler, Chantal Eickelmann, Petra Kleinbongard.
      Myocardial ischemia/reperfusion injury is reduced by cardioprotective adaptations such as local or remote ischemic conditioning. The cardioprotective stimuli activate signaling cascades, which converge on mitochondria and maintain the function of the organelles, which is critical for cell survival. The signaling cascades include not only extracellular molecules that activate sarcolemmal receptor-dependent or -independent protein kinases that signal at the plasma membrane or in the cytosol, but also involve kinases, which are located to or within mitochondria, phosphorylate mitochondrial target proteins, and thereby modify, e.g., respiration, the generation of reactive oxygen species, calcium handling, mitochondrial dynamics, mitophagy, or apoptosis. In the present review, we give a personal and opinionated overview of selected protein kinases, localized to/within myocardial mitochondria, and summarize the available data on their role in myocardial ischemia/reperfusion injury and protection from it. We highlight the regulation of mitochondrial function by these mitochondrial protein kinases.
    Keywords:  cardioprotection; ischemia; mitochondria; preconditioning; protein kinase; reperfusion
    DOI:  https://doi.org/10.3390/ijms25084491
  10. Adv Kidney Dis Health. 2024 Mar;pii: S2949-8139(23)00064-2. [Epub ahead of print]31(2): 127-132
    Hepato-Cardio-Renal Syndrome.
    Abhilash Koratala, Frederik Verbrugge, Amir Kazory.
      Hepatorenal syndrome has conventionally been regarded as a multisystem syndrome in which pathophysiologic pathways that link cirrhosis with impairment in kidney function are followed by dysfunction of several organs such as the heart. The advances in cardiac studies have helped diagnose more subtle cardiac abnormalities that would have otherwise remained unnoticed in a significant subset of patients with advanced liver disease and cirrhosis. Accumulating data suggests that in many instances, the cardiac dysfunction precedes and predicts development of kidney disease in such patients. These observations point to the heart as a key player in hepatorenal syndrome and challenge the notion that the cardiac abnormalities are either the consequence of aberrancies in hepatorenal interactions or have only minor effects. As such, the disturbances traditionally bundled within hepatorenal syndrome may indeed represent a hepatic form of cardiorenal syndrome whereby the liver affects the kidney in part through cardiorenal pathways (that is, hepato-cardio-renal syndrome).
    Keywords:  Cardiorenal syndrome; Cirrhotic cardiomyopathy; Heart failure; Hepatorenal syndrome
    DOI:  https://doi.org/10.1053/j.akdh.2023.07.002
  11. Skelet Muscle. 2024 Apr 20. 14(1): 7
    Dimorphic effect of TFE3 in determining mitochondrial and lysosomal content in muscle following denervation.
    Ashley N Oliveira, Jonathan M Memme, Jenna Wong, David A Hood.
       BACKGROUND: Muscle atrophy is a common consequence of the loss of innervation and is accompanied by mitochondrial dysfunction. Mitophagy is the adaptive process through which damaged mitochondria are removed via the lysosomes, which are regulated in part by the transcription factor TFE3. The role of lysosomes and TFE3 are poorly understood in muscle atrophy, and the effect of biological sex is widely underreported.
    METHODS: Wild-type (WT) mice, along with mice lacking TFE3 (KO), a transcriptional regulator of lysosomal and autophagy-related genes, were subjected to unilateral sciatic nerve denervation for up to 7 days, while the contralateral limb was sham-operated and served as an internal control. A subset of animals was treated with colchicine to capture mitophagy flux.
    RESULTS: WT females exhibited elevated oxygen consumption rates during active respiratory states compared to males, however this was blunted in the absence of TFE3. Females exhibited higher mitophagy flux rates and greater lysosomal content basally compared to males that was independent of TFE3 expression. Following denervation, female mice exhibited less muscle atrophy compared to male counterparts. Intriguingly, this sex-dependent muscle sparing was lost in the absence of TFE3. Denervation resulted in 45% and 27% losses of mitochondrial content in WT and KO males respectively, however females were completely protected against this decline. Decreases in mitochondrial function were more severe in WT females compared to males following denervation, as ROS emission was 2.4-fold higher. In response to denervation, LC3-II mitophagy flux was reduced by 44% in females, likely contributing to the maintenance of mitochondrial content and elevated ROS emission, however this response was dysregulated in the absence of TFE3. While both males and females exhibited increased lysosomal content following denervation, this response was augmented in females in a TFE3-dependent manner.
    CONCLUSIONS: Females have higher lysosomal content and mitophagy flux basally compared to males, likely contributing to the improved mitochondrial phenotype. Denervation-induced mitochondrial adaptations were sexually dimorphic, as females preferentially preserve content at the expense of function, while males display a tendency to maintain mitochondrial function. Our data illustrate that TFE3 is vital for the sex-dependent differences in mitochondrial function, and in determining the denervation-induced atrophy phenotype.
    Keywords:  Autophagy; Lysosomal biogenesis; Mitochondrial respiration; Mitophagy; ROS emission; Sex differences
    DOI:  https://doi.org/10.1186/s13395-024-00339-1
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