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Abedini A, Levinsohn J, Klötzer KA, Dumoulin B, Ma Z, Frederick J, Dhillon P, Balzer MS, Shrestha R, Liu H, Vitale S, Bergeson AM, Devalaraja-Narashimha K, Grandi P, Bhattacharyya T, Hu E, Pullen SS, Boustany-Kari CM, Guarnieri P, Karihaloo A, Traum D, Yan H, Coleman K, Palmer M, Sarov-Blat L, Morton L, Hunter CA, Kaestner KH, Li M, Susztak K. Single-cell multi-omic and spatial profiling of human kidneys implicates the fibrotic microenvironment in kidney disease progression. Nat Genet 2024; 56:1712-1724. [PMID: 39048792 PMCID: PMC11592391 DOI: 10.1038/s41588-024-01802-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2023] [Accepted: 05/15/2024] [Indexed: 07/27/2024]
Abstract
Kidneys are intricate three-dimensional structures in the body, yet the spatial and molecular principles of kidney health and disease remain inadequately understood. We generated high-quality datasets for 81 samples, including single-cell, single-nuclear, spot-level (Visium) and single-cell resolution (CosMx) spatial-RNA expression and single-nuclear open chromatin, capturing cells from healthy, diabetic and hypertensive diseased human kidneys. Combining these data, we identify cell types and map them to their locations within the tissue. Unbiased deconvolution of the spatial data identifies the following four distinct microenvironments: glomerular, immune, tubule and fibrotic. We describe the complex organization of microenvironments in health and disease and find that the fibrotic microenvironment is able to molecularly classify human kidneys and offers an improved prognosis compared to traditional histopathology. We provide a comprehensive spatially resolved molecular roadmap of the human kidney and the fibrotic process, demonstrating the clinical utility of spatial transcriptomics.
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Affiliation(s)
- Amin Abedini
- Renal, Electrolyte, and Hypertension Division, Department of Medicine, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, USA
- Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, USA
- Penn/CHOP Kidney Innovation Center, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, USA
- Department of Genetics, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, USA
| | - Jonathan Levinsohn
- Renal, Electrolyte, and Hypertension Division, Department of Medicine, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, USA
- Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, USA
- Penn/CHOP Kidney Innovation Center, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, USA
- Department of Genetics, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, USA
| | - Konstantin A Klötzer
- Renal, Electrolyte, and Hypertension Division, Department of Medicine, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, USA
- Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, USA
- Penn/CHOP Kidney Innovation Center, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, USA
- Department of Genetics, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, USA
| | - Bernhard Dumoulin
- Renal, Electrolyte, and Hypertension Division, Department of Medicine, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, USA
- Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, USA
- Penn/CHOP Kidney Innovation Center, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, USA
- Department of Genetics, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, USA
| | - Ziyuan Ma
- Renal, Electrolyte, and Hypertension Division, Department of Medicine, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, USA
- Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, USA
- Penn/CHOP Kidney Innovation Center, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, USA
| | - Julia Frederick
- Renal, Electrolyte, and Hypertension Division, Department of Medicine, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, USA
- Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, USA
- Penn/CHOP Kidney Innovation Center, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, USA
| | - Poonam Dhillon
- Renal, Electrolyte, and Hypertension Division, Department of Medicine, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, USA
- Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, USA
- Penn/CHOP Kidney Innovation Center, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, USA
| | - Michael S Balzer
- Renal, Electrolyte, and Hypertension Division, Department of Medicine, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, USA
- Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, USA
- Penn/CHOP Kidney Innovation Center, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, USA
- Nephrology, Charité - Universitätsmedizin, Berlin, Germany
| | - Rojesh Shrestha
- Renal, Electrolyte, and Hypertension Division, Department of Medicine, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, USA
- Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, USA
- Penn/CHOP Kidney Innovation Center, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, USA
| | - Hongbo Liu
- Renal, Electrolyte, and Hypertension Division, Department of Medicine, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, USA
- Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, USA
- Penn/CHOP Kidney Innovation Center, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, USA
| | - Steven Vitale
- Renal, Electrolyte, and Hypertension Division, Department of Medicine, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, USA
- Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, USA
- Penn/CHOP Kidney Innovation Center, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, USA
| | - Andi M Bergeson
- Renal, Electrolyte, and Hypertension Division, Department of Medicine, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, USA
- Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, USA
- Penn/CHOP Kidney Innovation Center, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, USA
- Department of Genetics, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, USA
| | | | - Paola Grandi
- Genomic Sciences, GSK-Cellzome, Heidelberg, Germany
| | | | - Erding Hu
- Research and Development, GSK, Crescent Drive, Philadelphia, PA, USA
| | - Steven S Pullen
- Department of Cardiometabolic Diseases Research, Boehringer Ingelheim Pharmaceuticals, Ridgefield, CT, USA
| | - Carine M Boustany-Kari
- Department of Cardiometabolic Diseases Research, Boehringer Ingelheim Pharmaceuticals, Ridgefield, CT, USA
| | - Paolo Guarnieri
- Department of Cardiometabolic Diseases Research, Boehringer Ingelheim Pharmaceuticals, Ridgefield, CT, USA
| | | | - Daniel Traum
- Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, USA
- Department of Genetics, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, USA
| | - Hanying Yan
- Department of Epidemiology, Biostatistics and Informatics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
| | - Kyle Coleman
- Department of Epidemiology, Biostatistics and Informatics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
| | - Matthew Palmer
- Department of Pathology and Laboratory Medicine, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, USA
| | - Lea Sarov-Blat
- Research and Development, GSK, Crescent Drive, Philadelphia, PA, USA
| | - Lori Morton
- Cardiovascular and Renal Research, Regeneron Pharmaceuticals Inc., Tarrytown, NY, USA
| | - Christopher A Hunter
- Department of Pathobiology, University of Pennsylvania School of Veterinary Medicine, Philadelphia, PA, USA
| | - Klaus H Kaestner
- Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, USA
- Department of Genetics, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, USA
| | - Mingyao Li
- Department of Epidemiology, Biostatistics and Informatics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
| | - Katalin Susztak
- Renal, Electrolyte, and Hypertension Division, Department of Medicine, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, USA.
- Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, USA.
- Penn/CHOP Kidney Innovation Center, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, USA.
- Department of Genetics, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, USA.
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Zhang L, Zhang Q, Liu S, Chen Y, Li R, Lin T, Yu C, Zhang H, Huang Z, Zhao X, Tan X, Li Z, Ye Z, Ma J, Zhang B, Wang W, Shi W, Liang X. DNA methyltransferase 1 may be a therapy target for attenuating diabetic nephropathy and podocyte injury. Kidney Int 2017; 92:140-153. [PMID: 28318634 DOI: 10.1016/j.kint.2017.01.010] [Citation(s) in RCA: 72] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2016] [Revised: 12/21/2016] [Accepted: 01/05/2017] [Indexed: 01/19/2023]
Affiliation(s)
- Li Zhang
- Division of Nephrology, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
| | | | - Shuangxin Liu
- Division of Nephrology, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Yuanhan Chen
- Division of Nephrology, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Ruizhao Li
- Division of Nephrology, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Ting Lin
- Division of Nephrology, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Chunping Yu
- Division of Nephrology, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Hong Zhang
- Division of Nephrology, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Zhongshun Huang
- Division of Nephrology, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Xinchen Zhao
- Division of Nephrology, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China; Southern Medical University, Guangzhou, China
| | - Xiaofan Tan
- Division of Nephrology, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Zhuo Li
- Division of Nephrology, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Zhiming Ye
- Division of Nephrology, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Jianchao Ma
- Division of Nephrology, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Bin Zhang
- Division of Nephrology, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Wenjian Wang
- Division of Nephrology, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Wei Shi
- Division of Nephrology, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China.
| | - Xinling Liang
- Division of Nephrology, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China.
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Wang J, Sun K, Shen Y, Xu Y, Xie J, Huang R, Zhang Y, Xu C, Zhang X, Wang R, Lin Y. DNA methylation is critical for tooth agenesis: implications for sporadic non-syndromic anodontia and hypodontia. Sci Rep 2016; 6:19162. [PMID: 26759063 PMCID: PMC4725352 DOI: 10.1038/srep19162] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2015] [Accepted: 12/02/2015] [Indexed: 02/05/2023] Open
Abstract
Hypodontia is caused by interactions among genetic, epigenetic, and environmental factors during tooth development, but the actual mechanism is unknown. DNA methylation now appears to play a significant role in abnormal developments, flawed phenotypes, and acquired diseases. Methylated DNA immunoprecipitation (MeDIP) has been developed as a new method of scanning large-scale DNA-methylation profiles within particular regions or in the entire genome. Here, we performed a genome-wide scan of paired DNA samples obtained from 4 patients lacking two mandibular incisors and 4 healthy controls with normal dentition. We scanned another female with non-syndromic anodontia and her younger brother with the same gene mutations of the PAX9,MSX1,AXIN2 and EDA, but without developmental abnormalities in the dentition. Results showed significant differences in the methylation level of the whole genome between the hypodontia and the normal groups. Nine genes were spotted, some of which have not been associated with dental development; these genes were related mainly to the development of cartilage, bone, teeth, and neural transduction, which implied a potential gene cascade network in hypodontia at the methylation level. This pilot study reveals the critical role of DNA methylation in hypodontia and might provide insights into developmental biology and the pathobiology of acquired diseases.
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Affiliation(s)
- Jing Wang
- Department of Stomatology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, No.301, Middle Yanchang Road, Shanghai 200072, P.R. China
| | - Ke Sun
- State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, No.14., 3rd Sec, Ren Min Nan Road, Chengdu 610041, P.R. China
| | - Yun Shen
- Department of Stomatology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, No.301, Middle Yanchang Road, Shanghai 200072, P.R. China
| | - Yuanzhi Xu
- Department of Stomatology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, No.301, Middle Yanchang Road, Shanghai 200072, P.R. China
| | - Jing Xie
- State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, No.14., 3rd Sec, Ren Min Nan Road, Chengdu 610041, P.R. China
| | - Renhuan Huang
- State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, No.14., 3rd Sec, Ren Min Nan Road, Chengdu 610041, P.R. China
| | - Yiming Zhang
- Department of Stomatology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, No.301, Middle Yanchang Road, Shanghai 200072, P.R. China
| | - Chenyuan Xu
- Department of Stomatology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, No.301, Middle Yanchang Road, Shanghai 200072, P.R. China
| | - Xu Zhang
- Department of Stomatology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, No.301, Middle Yanchang Road, Shanghai 200072, P.R. China
| | - Raorao Wang
- Department of Stomatology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, No.301, Middle Yanchang Road, Shanghai 200072, P.R. China
| | - Yunfeng Lin
- State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, No.14., 3rd Sec, Ren Min Nan Road, Chengdu 610041, P.R. China
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Shinzawa M, Yamamoto R, Nagasawa Y, Oseto S, Mori D, Tomida K, Hayashi T, Izumi M, Fukunaga M, Yamauchi A, Tsubakihara Y, Isaka Y. Comparison of methylprednisolone plus prednisolone with prednisolone alone as initial treatment in adult-onset minimal change disease: a retrospective cohort study. Clin J Am Soc Nephrol 2014; 9:1040-8. [PMID: 24721890 DOI: 10.2215/cjn.12331213] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
BACKGROUND AND OBJECTIVES Previous studies suggested that intravenous methylprednisolone possibly accelerates remission of proteinuria in adult-onset minimal change disease; its impact on relapse of proteinuria is unknown. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS This multicenter retrospective cohort study included 125 adult-onset minimal change disease patients diagnosed by kidney biopsy between 2000 and 2009 and treated initially with corticosteroid in five nephrology centers in Japan participating in the Study of Outcomes and Practice Patterns of Minimal Change Disease. Times to first remission and first relapse of proteinuria after initiating the first immunosuppressive therapy were compared between 65 patients with initial use of intravenous methylprednisolone followed by prednisolone and 60 patients with initial use of prednisolone alone using multivariate Cox proportional hazards models. After calculating the probability of receiving methylprednisolone and prednisolone using a logistic regression model (propensity score), the results were ascertained using propensity score-matched and -stratified models. RESULTS During the median 3.6 years of observation (interquartile range=2.0-6.9), all 65 patients in the methylprednisolone and prednisolone group achieved remission within 11 (8-20) days of the corticosteroid initiation, whereas in the prednisolone group, 58 of 60 patients (96.7%) achieved remission within 19 (12-37) days (P<0.001). After achieving first remission, 32 (49.2%) patients in the methylprednisolone and prednisolone group and 43 (74.1%) patients in the prednisolone group developed at least one relapse. Multivariate Cox proportional hazards models revealed that methylprednisolone and prednisolone use was significantly associated with early remission (multivariate-adjusted hazard ratio, 1.56; 95% confidence interval, 1.06 to 2.30) and lower incidence of relapse (0.50; 95% confidence interval, 0.29 to 0.85) compared with prednisolone use alone. These results were ascertained in propensity score-based models. No significant difference was observed in incidence of adverse events, including infection, aseptic osteonecrosis, cataract, diabetes, and gastrointestinal bleeding. CONCLUSIONS Initial use of methylprednisolone was associated with earlier remission and lower incidence of relapse in adult-onset minimal change disease patients. Efficacy of methylprednisolone should be evaluated in randomized controlled trials.
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Affiliation(s)
- Maki Shinzawa
- Departments of Geriatric Medicine and Nephrology, and
| | | | | | - Susumu Oseto
- Division of Nephrology, Department of Internal Medicine, Toyonaka Municipal Hospital, Toyonaka, Japan
| | - Daisuke Mori
- Division of Nephrology, Department of Internal Medicine, Osaka Rosai Hospital, Sakai, Osaka, Japan
| | - Kodo Tomida
- Department of Internal Medicine, Kansai Rosai Hospital, Amagasaki, Hyogo, Japan; and
| | - Terumasa Hayashi
- Department of Kidney Disease and Hypertension, Osaka General Medical Center, Osaka, Japan
| | - Masaaki Izumi
- Department of Internal Medicine, Kansai Rosai Hospital, Amagasaki, Hyogo, Japan; and
| | - Megumu Fukunaga
- Division of Nephrology, Department of Internal Medicine, Toyonaka Municipal Hospital, Toyonaka, Japan
| | - Atsushi Yamauchi
- Division of Nephrology, Department of Internal Medicine, Osaka Rosai Hospital, Sakai, Osaka, Japan
| | - Yoshiharu Tsubakihara
- Department of Kidney Disease and Hypertension, Osaka General Medical Center, Osaka, Japan Comprehensive Kidney Disease Research, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
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