Pub Date : 2024-10-18DOI: 10.1016/j.ajpath.2024.10.003
Samuel Mon-Wei Yu, Emily King, Miguel Fribourg, Susan Hartzell, Liam Tsou, Logan Gee, Vivette D D'Agati, Joshua M Thurman, John Cijiang He, Paolo Cravedi
Acute kidney injury (AKI) remains a major reason for hospitalization with limited therapeutic options. Although complement activation is implicated in AKI, the role of C5a receptor 1 (C5aR1) in kidney tubular cells is unclear. We used aristolochic acid nephropathy (AAN) and folic acid nephropathy models to establish the role of C5aR1 in kidney tubules during AKI in germline C5ar1-/- mice, myeloid cell-specific mice, and kidney tubule-specific C5ar1 knockout mice. After aristolochic acid and folic acid injection, C5ar1-/- mice had increased AKI severity and a higher degree of tubular injury. Macrophage depletion in C5ar1-/- mice or myeloid cell-specific C5ar1 deletion did not affect the outcomes of aristolochic acid-induced AKI. RNA-sequencing data from renal tubular epithelial cells (RTECs) showed that C5ar1 deletion was associated with the down-regulation of mitochondrial metabolism and ATP production transcriptional pathways. Metabolic studies confirmed reduced mitochondrial membrane potential at baseline and increased mitochondrial oxidative stress after injury in C5ar1-/- RTECs. Moreover, C5ar1-/- RTECs had enhanced glycolysis, glucose uptake, and lactate production on injury, corroborated by metabolomics analysis of kidneys from AAN mice. Kidney tubule-specific C5ar1 knockout mice recapitulated exacerbated AKI observed in C5ar1-/- mice in AAN and folic acid nephropathy. Our data indicate that C5aR1 signaling in kidney tubules exerts renoprotective effects against toxin-induced AKI by limiting overt glycolysis and maintaining mitochondrial function, revealing a novel link between the complement system and tubular cell metabolism.
急性肾损伤(AKI)仍然是住院治疗的一个主要原因,但治疗方案有限。虽然补体激活与 AKI 有关,但 C5a 受体 1(C5aR1)在肾小管细胞中的作用尚不清楚。我们利用马兜铃酸肾病(AAN)和叶酸肾病(FAN)模型,在种系C5ar1-/-小鼠、髓样细胞特异性和肾小管特异性C5ar1基因敲除小鼠中确定了AKI期间C5aR1在肾小管中的作用。注射马兜铃酸和叶酸后,C5ar1-/-小鼠的 AKI 严重程度增加,肾小管损伤程度加重。C5ar1-/-小鼠的巨噬细胞耗竭或骨髓细胞特异性C5ar1缺失不会影响AA诱导的AKI结果。RTECs的RNA测序数据显示,C5ar1缺失与线粒体代谢和ATP产生转录途径的下调有关。代谢研究证实,C5ar1-/- RTEC 的线粒体膜电位基线降低,损伤后线粒体氧化应激增加。此外,C5ar1-/- RTEC 在损伤后的糖酵解、葡萄糖摄取和乳酸生成均增强,AAN 小鼠肾脏的代谢组学分析也证实了这一点。肾小管特异性 C5ar1 基因敲除小鼠再现了在 C5ar1-/- AAN 和 FAN 小鼠中观察到的加重的 AKI。我们的数据表明,肾小管中的 C5aR1 信号通过限制明显的糖酵解和维持线粒体功能,对毒素诱导的 AKI 发挥肾保护作用,揭示了补体系统与肾小管细胞代谢之间的新联系。
{"title":"A Newly Identified Protective Role of C5a Receptor 1 in Kidney Tubules against Toxin-Induced Acute Kidney Injury.","authors":"Samuel Mon-Wei Yu, Emily King, Miguel Fribourg, Susan Hartzell, Liam Tsou, Logan Gee, Vivette D D'Agati, Joshua M Thurman, John Cijiang He, Paolo Cravedi","doi":"10.1016/j.ajpath.2024.10.003","DOIUrl":"10.1016/j.ajpath.2024.10.003","url":null,"abstract":"<p><p>Acute kidney injury (AKI) remains a major reason for hospitalization with limited therapeutic options. Although complement activation is implicated in AKI, the role of C5a receptor 1 (C5aR1) in kidney tubular cells is unclear. We used aristolochic acid nephropathy (AAN) and folic acid nephropathy models to establish the role of C5aR1 in kidney tubules during AKI in germline C5ar1<sup>-/-</sup> mice, myeloid cell-specific mice, and kidney tubule-specific C5ar1 knockout mice. After aristolochic acid and folic acid injection, C5ar1<sup>-/-</sup> mice had increased AKI severity and a higher degree of tubular injury. Macrophage depletion in C5ar1<sup>-/-</sup> mice or myeloid cell-specific C5ar1 deletion did not affect the outcomes of aristolochic acid-induced AKI. RNA-sequencing data from renal tubular epithelial cells (RTECs) showed that C5ar1 deletion was associated with the down-regulation of mitochondrial metabolism and ATP production transcriptional pathways. Metabolic studies confirmed reduced mitochondrial membrane potential at baseline and increased mitochondrial oxidative stress after injury in C5ar1<sup>-/-</sup> RTECs. Moreover, C5ar1<sup>-/-</sup> RTECs had enhanced glycolysis, glucose uptake, and lactate production on injury, corroborated by metabolomics analysis of kidneys from AAN mice. Kidney tubule-specific C5ar1 knockout mice recapitulated exacerbated AKI observed in C5ar1<sup>-/-</sup> mice in AAN and folic acid nephropathy. Our data indicate that C5aR1 signaling in kidney tubules exerts renoprotective effects against toxin-induced AKI by limiting overt glycolysis and maintaining mitochondrial function, revealing a novel link between the complement system and tubular cell metabolism.</p>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":null,"pages":null},"PeriodicalIF":4.7,"publicationDate":"2024-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142455939","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-12DOI: 10.1016/j.ajpath.2024.10.002
{"title":"This Month in AJP.","authors":"","doi":"10.1016/j.ajpath.2024.10.002","DOIUrl":"https://doi.org/10.1016/j.ajpath.2024.10.002","url":null,"abstract":"","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":null,"pages":null},"PeriodicalIF":4.7,"publicationDate":"2024-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142455942","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-11DOI: 10.1016/j.ajpath.2024.10.001
Chhavi Chauhan, George Currie
{"title":"The Impact of Generative Artificial Intelligence on Research Integrity in Scholarly Publishing.","authors":"Chhavi Chauhan, George Currie","doi":"10.1016/j.ajpath.2024.10.001","DOIUrl":"https://doi.org/10.1016/j.ajpath.2024.10.001","url":null,"abstract":"","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":null,"pages":null},"PeriodicalIF":4.7,"publicationDate":"2024-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142455941","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-26DOI: 10.1016/j.ajpath.2024.09.006
Danielle Janosevic, Thomas De Luca, Michael T Eadon
Single-cell RNA sequencing (scRNA-seq) has led to major advances in our understanding of proximal tubule subtypes in health and disease. The proximal tubule serves essential functions in overall homeostasis, but pathologic or physiological perturbations can affect its transcriptomic signature and corresponding tasks. These alterations in proximal tubular cells are often described within a scRNA-seq atlas as cell states, which are pathophysiological subclassifications based on molecular and morphologic changes in a cell's response to that injury compared with its native state. This review describes the major cell states defined in the Kidney Precision Medicine Project's scRNA-seq atlas. The review then identifies the overlap between the Kidney Precision Medicine Project and other seminal works that may use different nomenclature or cluster proximal tubule cells at different resolutions to define cell state subtypes. The goal is for the reader to understand the key transcriptomic markers of important cellular injury and regeneration processes across this highly dynamic and evolving field.
{"title":"The Kidney Precision Medicine Project and Single-Cell Biology of the Injured Proximal Tubule.","authors":"Danielle Janosevic, Thomas De Luca, Michael T Eadon","doi":"10.1016/j.ajpath.2024.09.006","DOIUrl":"10.1016/j.ajpath.2024.09.006","url":null,"abstract":"<p><p>Single-cell RNA sequencing (scRNA-seq) has led to major advances in our understanding of proximal tubule subtypes in health and disease. The proximal tubule serves essential functions in overall homeostasis, but pathologic or physiological perturbations can affect its transcriptomic signature and corresponding tasks. These alterations in proximal tubular cells are often described within a scRNA-seq atlas as cell states, which are pathophysiological subclassifications based on molecular and morphologic changes in a cell's response to that injury compared with its native state. This review describes the major cell states defined in the Kidney Precision Medicine Project's scRNA-seq atlas. The review then identifies the overlap between the Kidney Precision Medicine Project and other seminal works that may use different nomenclature or cluster proximal tubule cells at different resolutions to define cell state subtypes. The goal is for the reader to understand the key transcriptomic markers of important cellular injury and regeneration processes across this highly dynamic and evolving field.</p>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":null,"pages":null},"PeriodicalIF":4.7,"publicationDate":"2024-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142339402","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-26DOI: 10.1016/j.ajpath.2024.09.002
Monir Modaresinejad, Xiaojuan Yang, Mohammad Ali Mohammad Nezhady, Tang Zhu, Emmanuel Bajon, Xin Hou, Houda Tahiri, Pierre Hardy, José Carlos Rivera, Pierre Lachapelle, Sylvain Chemtob
The subretina, composed of the choroid and the retinal pigment epithelium (RPE), bears a critical role in proper vision. In addition to phagocytosis of photoreceptor debris, the RPE shuttles oxygen and nutrients to the neuroretina. For their own energy production, RPE cells mainly rely on lactate, a major by-product of glycolysis. Lactate, in turn, is believed to convey most of its biological effects via the hydroxycarboxylic acid receptor 1 (HCAR1). Here, the lactate-specific receptor, HCAR1, is found to be exclusively expressed in the RPE cells within the subretina, and Hcar1-/- mice exhibit a substantially thinner choroidal vasculature during development. Notably, the angiogenic properties of lactate on the choroid are impacted by the absence of Hcar1. HCAR1-deficient mice exhibit elevated endoplasmic reticulum stress along with eukaryotic initiation factor 2α phosphorylation, a significant decrease in the global protein translation rate, and a lower proliferation rate of choroidal vasculature. Strikingly, inhibition of the integrated stress response using an inhibitor that reverses the effect of eukaryotic initiation factor 2α phosphorylation restores protein translation and rescues choroidal thinning. These results provide evidence that lactate signalling via HCAR1 is important for choroidal development/angiogenesis and highlight the importance of this receptor in establishing mature vision.
{"title":"Endoplasmic Reticulum Stress Delays Choroid Development in the HCAR1 Knockout Mouse.","authors":"Monir Modaresinejad, Xiaojuan Yang, Mohammad Ali Mohammad Nezhady, Tang Zhu, Emmanuel Bajon, Xin Hou, Houda Tahiri, Pierre Hardy, José Carlos Rivera, Pierre Lachapelle, Sylvain Chemtob","doi":"10.1016/j.ajpath.2024.09.002","DOIUrl":"https://doi.org/10.1016/j.ajpath.2024.09.002","url":null,"abstract":"<p><p>The subretina, composed of the choroid and the retinal pigment epithelium (RPE), bears a critical role in proper vision. In addition to phagocytosis of photoreceptor debris, the RPE shuttles oxygen and nutrients to the neuroretina. For their own energy production, RPE cells mainly rely on lactate, a major by-product of glycolysis. Lactate, in turn, is believed to convey most of its biological effects via the hydroxycarboxylic acid receptor 1 (HCAR1). Here, the lactate-specific receptor, HCAR1, is found to be exclusively expressed in the RPE cells within the subretina, and Hcar1<sup>-/-</sup> mice exhibit a substantially thinner choroidal vasculature during development. Notably, the angiogenic properties of lactate on the choroid are impacted by the absence of Hcar1. HCAR1-deficient mice exhibit elevated endoplasmic reticulum stress along with eukaryotic initiation factor 2α phosphorylation, a significant decrease in the global protein translation rate, and a lower proliferation rate of choroidal vasculature. Strikingly, inhibition of the integrated stress response using an inhibitor that reverses the effect of eukaryotic initiation factor 2α phosphorylation restores protein translation and rescues choroidal thinning. These results provide evidence that lactate signalling via HCAR1 is important for choroidal development/angiogenesis and highlight the importance of this receptor in establishing mature vision.</p>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":null,"pages":null},"PeriodicalIF":4.7,"publicationDate":"2024-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142339396","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-26DOI: 10.1016/j.ajpath.2024.09.005
Biyang Xu, Vladislav Levchenko, Adrian Zietara, Sarah Fan, Christine A Klemens, Alexander Staruschenko
Maintaining acid-base homeostasis is critical for normal physiological function. The kidneys are essential for regulating acid-base homeostasis through maintaining systemic bicarbonate concentration. Chronic metabolic acidosis is an independent risk factor for chronic kidney diseases. Renal inwardly rectifying potassium channel Kir5.1 plays an essential role in maintaining resting membrane potential. Patients with loss-of-function mutations in the KCNJ16 gene, which encodes Kir5.1, reveal tubulopathy with hypokalemia, salt wasting, and hearing loss. Importantly, these mutations also disrupt acid-base balance, particularly causing metabolic acidosis. This study aimed to use Dahl salt-sensitive rats with a knockout of the Kcnj16 gene (SSKcnj16-/-) to investigate how the deletion of Kir5.1 affects the regulation of acid-base balance in salt-sensitive hypertension. Results indicated that SSKcnj16-/- rats displayed metabolic acidosis under a normal salt diet. Further analysis using RNA sequencing and Western blot analysis showed unchanged expression of proteins responsible for ammonia metabolism in the kidney of SSKcnj16-/- rats despite observed acidosis. However, there was a significant increase in the expression of bicarbonate transporter NBCe1, where there was a significant decrease in pendrin. In conclusion, the current study demonstrated that the loss of Kir5.1 impairs the sensitivity of ammonia metabolism in the kidney in response to metabolic acidosis, which provides mechanistic insights into developing potential therapeutics for conditions involving hypokalemia and acid-base abnormalities.
{"title":"Role of K<sub>ir</sub>5.1 (Kcnj16) Channels in Regulating Renal Ammonia Metabolism during Metabolic Acidosis in Dahl Salt-Sensitive Rats.","authors":"Biyang Xu, Vladislav Levchenko, Adrian Zietara, Sarah Fan, Christine A Klemens, Alexander Staruschenko","doi":"10.1016/j.ajpath.2024.09.005","DOIUrl":"10.1016/j.ajpath.2024.09.005","url":null,"abstract":"<p><p>Maintaining acid-base homeostasis is critical for normal physiological function. The kidneys are essential for regulating acid-base homeostasis through maintaining systemic bicarbonate concentration. Chronic metabolic acidosis is an independent risk factor for chronic kidney diseases. Renal inwardly rectifying potassium channel K<sub>ir</sub>5.1 plays an essential role in maintaining resting membrane potential. Patients with loss-of-function mutations in the KCNJ16 gene, which encodes K<sub>ir</sub>5.1, reveal tubulopathy with hypokalemia, salt wasting, and hearing loss. Importantly, these mutations also disrupt acid-base balance, particularly causing metabolic acidosis. This study aimed to use Dahl salt-sensitive rats with a knockout of the Kcnj16 gene (SS<sup>Kcnj16-/-</sup>) to investigate how the deletion of K<sub>ir</sub>5.1 affects the regulation of acid-base balance in salt-sensitive hypertension. Results indicated that SS<sup>Kcnj16-/-</sup> rats displayed metabolic acidosis under a normal salt diet. Further analysis using RNA sequencing and Western blot analysis showed unchanged expression of proteins responsible for ammonia metabolism in the kidney of SS<sup>Kcnj16-/-</sup> rats despite observed acidosis. However, there was a significant increase in the expression of bicarbonate transporter NBCe1, where there was a significant decrease in pendrin. In conclusion, the current study demonstrated that the loss of K<sub>ir</sub>5.1 impairs the sensitivity of ammonia metabolism in the kidney in response to metabolic acidosis, which provides mechanistic insights into developing potential therapeutics for conditions involving hypokalemia and acid-base abnormalities.</p>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":null,"pages":null},"PeriodicalIF":4.7,"publicationDate":"2024-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142339401","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-26DOI: 10.1016/j.ajpath.2024.08.014
Rachel V Guest, Benjamin Goeppert, Jean-Charles Nault, Daniela Sia
Cholangiocarcinomas are a highly heterogeneous group of malignancies that, despite recent progress in the understanding of their molecular pathogenesis and clinical management, continue to pose a major challenge to public health. The traditional view posits that cholangiocarcinomas derive from the neoplastic transformation of cholangiocytes lining the biliary tree. However, increasing genetic and experimental evidence has recently pointed to a more complex, and nuanced, scenario for the potential cell of origin of cholangiocarcinomas. Hepatocytes as well as hepatic stem/progenitor cells are being considered as additional potential sources, depending on microenvironmental contexts, including liver injury. The hypothesis of potentially diverse cells of origin for cholangiocarcinoma, albeit controversial, is certainly not surprising given the plasticity of the cells populating the liver as well as the existence of liver cancer subtypes with mixed histologic and molecular features. This review carefully examines the current pathologic, genomic, and experimental evidence supporting the existence of multiple cells of origin of liver and biliary tract cancers, with particular focus on cholangiocarcinoma and combined hepatocellular-cholangiocarcinoma.
{"title":"Morphomolecular Pathology and Genomic Insights into the Cells of Origin of Cholangiocarcinoma and Combined Hepatocellular-Cholangiocarcinoma.","authors":"Rachel V Guest, Benjamin Goeppert, Jean-Charles Nault, Daniela Sia","doi":"10.1016/j.ajpath.2024.08.014","DOIUrl":"10.1016/j.ajpath.2024.08.014","url":null,"abstract":"<p><p>Cholangiocarcinomas are a highly heterogeneous group of malignancies that, despite recent progress in the understanding of their molecular pathogenesis and clinical management, continue to pose a major challenge to public health. The traditional view posits that cholangiocarcinomas derive from the neoplastic transformation of cholangiocytes lining the biliary tree. However, increasing genetic and experimental evidence has recently pointed to a more complex, and nuanced, scenario for the potential cell of origin of cholangiocarcinomas. Hepatocytes as well as hepatic stem/progenitor cells are being considered as additional potential sources, depending on microenvironmental contexts, including liver injury. The hypothesis of potentially diverse cells of origin for cholangiocarcinoma, albeit controversial, is certainly not surprising given the plasticity of the cells populating the liver as well as the existence of liver cancer subtypes with mixed histologic and molecular features. This review carefully examines the current pathologic, genomic, and experimental evidence supporting the existence of multiple cells of origin of liver and biliary tract cancers, with particular focus on cholangiocarcinoma and combined hepatocellular-cholangiocarcinoma.</p>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":null,"pages":null},"PeriodicalIF":4.7,"publicationDate":"2024-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142339400","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-25DOI: 10.1016/j.ajpath.2024.08.013
Danielle Janosevic, Thomas De Luca, Ricardo Melo Ferreira, Debora L Gisch, Ying-Hua Cheng, Takashi Hato, Jinghui Luo, Yingbao Yang, Jeffrey B Hodgin, Carrie L Phillips, Pierre C Dagher, Michael T Eadon
Acute kidney injury (AKI) is an important contributor to the development of chronic kidney disease (CKD). There is a need to understand molecular mediators that drive recovery and progression to CKD. In particular, the regulatory role of miRNAs in AKI is poorly understood. miRNA and mRNA sequencing were performed on biobanked human kidney tissues obtained in the routine care of subjects with a diagnosis of AKI, minimal change disease, or without known kidney disease in nephrectomy tissue. mRNA analysis revealed that nephrectomy tissues exhibited an injury signature similar to that of AKI and not identified in minimal change disease samples. The transcriptomic signature of human AKI was enriched in pathways involved in cell adhesion, epithelial-to-mesenchymal transition, and cell cycle arrest (eg, CDH6, ITGB6, CDKN1A). In AKI, up-regulation of miR-146a, miR-155, miR-142, and miR-122 was associated with pathways involved in immune cell recruitment, inflammation, and epithelial-to-mesenchymal transition. miR-122 and miR-146 were associated with down-regulation of DDR2 and IGFBP6, which are genes involved in the recovery and progression of kidney disease. These data provide integrated miRNA signatures that complement mRNA and other epigenetic data available in kidney atlases.
急性肾损伤(AKI)是导致慢性肾脏病(CKD)发展的重要因素。我们需要了解推动恢复和发展为慢性肾脏病的分子介质。mRNA分析表明,Ref组织表现出与AKI相似的损伤特征,但在MCD样本中没有发现。人类 AKI 的转录组特征富含参与细胞粘附、上皮细胞向间质转化和细胞周期停滞的通路(如 CDH6、ITGB6、CDKN1A)。在 AKI 中,miR-146a、miR-155、miR-142、miR-122 的上调与免疫细胞招募、炎症和上皮细胞向间质转化的通路相关。这些数据提供了综合的 miRNA 特征,补充了肾脏图谱中的 mRNA 和其他表观遗传学数据。
{"title":"miRNA and mRNA Signatures in Human Acute Kidney Injury Tissue.","authors":"Danielle Janosevic, Thomas De Luca, Ricardo Melo Ferreira, Debora L Gisch, Ying-Hua Cheng, Takashi Hato, Jinghui Luo, Yingbao Yang, Jeffrey B Hodgin, Carrie L Phillips, Pierre C Dagher, Michael T Eadon","doi":"10.1016/j.ajpath.2024.08.013","DOIUrl":"10.1016/j.ajpath.2024.08.013","url":null,"abstract":"<p><p>Acute kidney injury (AKI) is an important contributor to the development of chronic kidney disease (CKD). There is a need to understand molecular mediators that drive recovery and progression to CKD. In particular, the regulatory role of miRNAs in AKI is poorly understood. miRNA and mRNA sequencing were performed on biobanked human kidney tissues obtained in the routine care of subjects with a diagnosis of AKI, minimal change disease, or without known kidney disease in nephrectomy tissue. mRNA analysis revealed that nephrectomy tissues exhibited an injury signature similar to that of AKI and not identified in minimal change disease samples. The transcriptomic signature of human AKI was enriched in pathways involved in cell adhesion, epithelial-to-mesenchymal transition, and cell cycle arrest (eg, CDH6, ITGB6, CDKN1A). In AKI, up-regulation of miR-146a, miR-155, miR-142, and miR-122 was associated with pathways involved in immune cell recruitment, inflammation, and epithelial-to-mesenchymal transition. miR-122 and miR-146 were associated with down-regulation of DDR2 and IGFBP6, which are genes involved in the recovery and progression of kidney disease. These data provide integrated miRNA signatures that complement mRNA and other epigenetic data available in kidney atlases.</p>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":null,"pages":null},"PeriodicalIF":4.7,"publicationDate":"2024-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142339399","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-25DOI: 10.1016/j.ajpath.2024.09.003
Emmanuelle Frampton, Priyanka Som, Brittany Hill, Alexander Yu, Marina Naval-Sanchez, Chistian M Nefzger, Ivar Noordstra, Emma Gordon, Lilian Schimmel
Vascular retinopathy, characterized by abnormal blood vessel growth in the retina, frequently results in vision impairment or loss. Neovascular tufts, a distinctive pathologic feature of this condition, are highly leaky blood vessel structures, exacerbating secondary complications. Despite their clinical significance, the mechanisms underlying tuft development are not fully elucidated, posing challenges for effective management and treatment of vascular retinopathy. This study investigates the role of c-Src in neovascular tuft formation. Although c-Src has been acknowledged as a pivotal regulator in developmental angiogenesis within the retinal vasculature, its specific role in governing pathologic retinal angiogenesis remains to be fully understood. The oxygen-induced retinopathy model was used for neovascular tuft formation in both Cre-mediated vascular-specific c-Src knockout mice and wild-type littermates. High-resolution imaging and analysis of isolated retinas were conducted. c-Src depletion demonstrated a significant reduction in neovascular tufts within the oxygen-induced retinopathy model. This decrease in tuft formation was observed independently of any alterations in cell death, cell proliferation, or cell adhesion, and the absence of c-Src did not impact tuft pericyte coverage and junctional morphology. These findings underline the critical role of c-Src in the pathogenesis of neovascular tufts in vascular retinopathy. Understanding the molecular mechanisms involving c-Src may offer valuable insights for the development of targeted therapies aimed at mitigating vision-threatening complications associated with retinopathy.
{"title":"Endothelial c-Src Mediates Neovascular Tuft Formation in Oxygen-Induced Retinopathy.","authors":"Emmanuelle Frampton, Priyanka Som, Brittany Hill, Alexander Yu, Marina Naval-Sanchez, Chistian M Nefzger, Ivar Noordstra, Emma Gordon, Lilian Schimmel","doi":"10.1016/j.ajpath.2024.09.003","DOIUrl":"https://doi.org/10.1016/j.ajpath.2024.09.003","url":null,"abstract":"<p><p>Vascular retinopathy, characterized by abnormal blood vessel growth in the retina, frequently results in vision impairment or loss. Neovascular tufts, a distinctive pathologic feature of this condition, are highly leaky blood vessel structures, exacerbating secondary complications. Despite their clinical significance, the mechanisms underlying tuft development are not fully elucidated, posing challenges for effective management and treatment of vascular retinopathy. This study investigates the role of c-Src in neovascular tuft formation. Although c-Src has been acknowledged as a pivotal regulator in developmental angiogenesis within the retinal vasculature, its specific role in governing pathologic retinal angiogenesis remains to be fully understood. The oxygen-induced retinopathy model was used for neovascular tuft formation in both Cre-mediated vascular-specific c-Src knockout mice and wild-type littermates. High-resolution imaging and analysis of isolated retinas were conducted. c-Src depletion demonstrated a significant reduction in neovascular tufts within the oxygen-induced retinopathy model. This decrease in tuft formation was observed independently of any alterations in cell death, cell proliferation, or cell adhesion, and the absence of c-Src did not impact tuft pericyte coverage and junctional morphology. These findings underline the critical role of c-Src in the pathogenesis of neovascular tufts in vascular retinopathy. Understanding the molecular mechanisms involving c-Src may offer valuable insights for the development of targeted therapies aimed at mitigating vision-threatening complications associated with retinopathy.</p>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":null,"pages":null},"PeriodicalIF":4.7,"publicationDate":"2024-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142339397","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-24DOI: 10.1016/j.ajpath.2024.07.023
Inyoung Cheon, Minwook Kim, Kang Ho Kim, Sungjin Ko
Cholestasis, characterized by impaired bile flow, is associated with an increased risk of cholangiocarcinoma (CCA), a malignancy originating from the biliary epithelium and hepatocytes. Hepatic nuclear receptors (NRs) are pivotal in regulating bile acid and metabolic homeostasis, and their dysregulation is implicated in cholestatic liver diseases and the progression of liver cancer. This review elucidates the role of various hepatic NRs in the pathogenesis of cholestasis-to-CCA progression. We explore their impact on bile acid metabolism as well as their interactions with other signaling pathways implicated in CCA development. Additionally, we introduce available murine models of cholestasis/primary sclerosing cholangitis leading to CCA and discuss the clinical potential of targeting hepatic NRs as a promising approach for the prevention and treatment of cholestatic liver diseases and CCA. Understanding the complex interplay between hepatic NRs and cholestasis-to-CCA pathology holds promise for the development of novel preventive and therapeutic strategies for this devastating disease.
胆汁淤积症的特点是胆汁流动受阻,它与胆管癌(CCA)风险增加有关,胆管癌是一种源自胆道上皮和肝细胞的恶性肿瘤。肝脏核受体(NRs)在调节胆汁酸和代谢平衡中起着关键作用,它们的失调与胆汁淤积性肝病和肝癌的进展有关。本综述阐明了各种肝脏 NRs 在胆汁淤积性肝癌进展的发病机制中的作用。我们探讨了它们对胆汁酸代谢的影响,以及它们与其他涉及 CCA 发展的信号通路之间的相互作用。此外,我们还介绍了现有的胆汁淤积症/原发性硬化性胆管炎(PSC)导致 CCA 的小鼠模型,并讨论了靶向肝 NRs 作为预防和治疗胆汁淤积性肝病和 CCA 的一种有前景的方法的临床潜力。了解肝NRs与胆汁淤积性肝病到CCA病理之间复杂的相互作用,有望为这一毁灭性疾病开发出新的预防和治疗策略。
{"title":"Hepatic Nuclear Receptors in Cholestasis-to-Cholangiocarcinoma Pathology.","authors":"Inyoung Cheon, Minwook Kim, Kang Ho Kim, Sungjin Ko","doi":"10.1016/j.ajpath.2024.07.023","DOIUrl":"10.1016/j.ajpath.2024.07.023","url":null,"abstract":"<p><p>Cholestasis, characterized by impaired bile flow, is associated with an increased risk of cholangiocarcinoma (CCA), a malignancy originating from the biliary epithelium and hepatocytes. Hepatic nuclear receptors (NRs) are pivotal in regulating bile acid and metabolic homeostasis, and their dysregulation is implicated in cholestatic liver diseases and the progression of liver cancer. This review elucidates the role of various hepatic NRs in the pathogenesis of cholestasis-to-CCA progression. We explore their impact on bile acid metabolism as well as their interactions with other signaling pathways implicated in CCA development. Additionally, we introduce available murine models of cholestasis/primary sclerosing cholangitis leading to CCA and discuss the clinical potential of targeting hepatic NRs as a promising approach for the prevention and treatment of cholestatic liver diseases and CCA. Understanding the complex interplay between hepatic NRs and cholestasis-to-CCA pathology holds promise for the development of novel preventive and therapeutic strategies for this devastating disease.</p>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":null,"pages":null},"PeriodicalIF":4.7,"publicationDate":"2024-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142339398","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}