scholarly journals Single Cell Profiling of Acute Kidney Injury Reveals Novel Transcriptional Signatures, Mixed Identities and Epithelial-to-Stromal Crosstalk

2019 ◽  
Author(s):  
Valeria Rudman-Melnick ◽  
Mike Adam ◽  
Andrew Potter ◽  
Saagar M. Chokshi ◽  
Qing Ma ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Single Cell ◽  
Stromal Cells ◽  
Gene Activation ◽  
Kidney Injury ◽  
Rapid Decline ◽  
Renal Tubules ◽  
Developmental Gene ◽  
Single Cell Profiling

SummaryAcute kidney injury (AKI) is a rapid decline of renal function, with an incidence of up to 67% of intensive care unit patients. Current treatments are merely supportive, emphasizing the need for deeper understanding that could lead to improved therapies. We used single cell RNA sequencing, in situ hybridization and protein expression analyses to create comprehensive renal cell specific transcriptional profiles of multiple AKI stages. We revealed that AKI induces marked dedifferentiation, renal developmental gene activation and mixed identities in injured renal tubules. Moreover, we identified potential pathologic crosstalk between epithelial and stromal cells, and several novel genes involved in AKI. We also demonstrated the definitive effects of age on AKI outcome, and showed that renal developmental genes hold a potential as novel AKI markers. Moreover, our study provides the resource power which will aid in unraveling the molecular genetics of AKI.

scholarly journals Mitophagy in Acute Kidney Injury and Kidney Repair

Cells ◽  
2020 ◽  
Vol 9 (2) ◽  
pp. 338 ◽  
Author(s):  
Ying Wang ◽  
Juan Cai ◽  
Chengyuan Tang ◽  
Zheng Dong
Keyword(s):  
Acute Kidney Injury ◽  
Kidney Disease ◽  
Molecular Mechanisms ◽  
Therapeutic Potential ◽  
Kidney Injury ◽  
Future Research ◽  
Rapid Decline ◽  
Renal Tubules ◽  
Renal Tubular Cells

Acute kidney injury (AKI) is a major kidney disease characterized by rapid decline of renal function. Besides its acute consequence of high mortality, AKI has recently been recognized as an independent risk factor for chronic kidney disease (CKD). Maladaptive or incomplete repair of renal tubules after severe or episodic AKI leads to renal fibrosis and, eventually, CKD. Recent studies highlight a key role of mitochondrial pathology in AKI development and abnormal kidney repair after AKI. As such, timely elimination of damaged mitochondria in renal tubular cells represents an important quality control mechanism for cell homeostasis and survival during kidney injury and repair. Mitophagy is a selective form of autophagy that selectively removes redundant or damaged mitochondria. Here, we summarize our recent understanding on the molecular mechanisms of mitophagy, discuss the role of mitophagy in AKI development and kidney repair after AKI, and present future research directions and therapeutic potential.

scholarly journals Systemic analysis of tissue cells potentially vulnerable to SARS-CoV-2 infection by the protein-proofed single-cell RNA profiling of ACE2, TMPRSS2 and Furin proteases

2020 ◽  
Author(s):  
Lulin Zhou ◽  
Zubiao Niu ◽  
Xiaoyi Jiang ◽  
Zhengrong Zhang ◽  
You Zheng ◽  
...  
Keyword(s):  
Single Cell ◽  
Stromal Cells ◽  
Clinical Manifestations ◽  
Kidney Injury ◽  
Apical Region ◽  
Rna Profiling ◽  
Systemic Analysis ◽  
Tissue Cells ◽  
Stomach Ph ◽  
Novel Coronavirus

ABSTRACTSingle-cell RNA profiling of ACE2, the SARS-CoV-2 receptor, had proposed multiple tissue cells as the potential targets of SARS-CoV-2, the novel coronavirus causing the COVID-19 pandemic. However, most were not echoed by the patients’ clinical manifestations, largely due to the lack of protein expression information of ACE2 and co-factors. Here, we incorporated the protein information to analyse the expression of ACE2, together with TMPRSS2 and Furin, two proteases assisting SARS-CoV-2 infection, at single cell level in situ, which we called protein-proofed single-cell RNA (pscRNA) profiling. Systemic analysis across 36 tissues revealed a rank list of candidate cells potentially vulnerable to SARS-CoV-2. The top targets are lung AT2 cells and macrophages, then cardiomyocytes and adrenal gland stromal cells, followed by stromal cells in testis, ovary and thyroid. Whereas, the polarized kidney proximal tubule cells, liver cholangiocytes and intestinal enterocytes are less likely to be the primary SARS-CoV-2 targets as ACE2 localizes at the apical region of cells, where the viruses may not readily reach. Actually, the stomach may constitute a physical barrier against SARS-CoV-2 as the acidic environment in normal stomach (pH < 2.0) could completely inactivate SARS-CoV-2 pseudo-viruses. These findings are in concert with the clinical characteristics of prominent lung symptoms, frequent heart injury, and uncommon intestinal symptoms and acute kidney injury. Together, we provide a comprehensive view on the potential SARS-CoV-2 targets by pscRNA profiling, and propose that, in addition to acute respiratory distress syndrome, attentions should also be paid to the potential injuries in cardiovascular, endocrine and reproductive systems during the treatment of COVID-19 patients.

scholarly journals Evaluation of Aetiology and Outcome of Acute Kidney Injury in a Tertiary Care Hospital of India- A Prospective Observational Study

2020 ◽  
Author(s):  
VS Gaurav Narayan ◽  
SG Ramya ◽  
Sonal Rajesh Kumar ◽  
SK Nellaiappa Ganesan
Keyword(s):  
Acute Kidney Injury ◽  
Intensive Care ◽  
Observational Study ◽  
Prospective Observational Study ◽  
Tertiary Care ◽  
Kidney Injury ◽  
Rapid Decline ◽  
Care Hospital ◽  
Medical Intensive Care

Introduction: The Acute Kidney Injury (AKI) is a rapid decline in renal filtration function. The aetiological spectrum, prevalence of AKI and outcome is highly variable. This variation exists due to the difference in the criteria used, study population and demographic features. Huge differences are noted when AKI is compared in developing and developed countries. Hence, it is important to analyse the spectrum of AKI to facilitate earlier diagnosis and treatment which shall help in improving the outcome. Aim: To study the prevalence, aetiology and outcome of AKI in the medical intensive care. Materials and Methods: This was a prospective observational study conducted in a medical intensive care for 18 months where 1490 patients were screened and 403 patients were included as AKI by KDIGO criteria. History, examination, appropriate investigations and treatment details including dialysis were noted. The serum creatinine levels were obtained every day, to know the time of onset of AKI, at the time of death or discharge, and after one month for patients who turned up for follow-up. Patients were categorised based on outcome as survivors and nonsurvivors. Survivors were divided into as fully recovered and partially recovered and those who left the Intensive Care Unit (ICU) against medical advice were termed as lost to follow-up. Results: A total of 403 patients (27.04% of 1490) of medical intensive care admissions were found to have AKI. Sepsis was the most common cause of AKI. At the end of the month, 78.4% of AKI patients fully recovered, 1.2% partially recovered and the mortality was 14.9%. Mortality was higher in AKI associated with chronic medical conditions like cardiac failure, chronic liver disease and stroke. Conclusion: If treated early, AKI is mostly reversible. Regional differences in AKI should be studied extensively and local guidelines should be formulated by experts for prevention and early treatment, to improve the disease outcome.

scholarly journals Reproducible Large-Scale Isolation of Exosomes from Adipose Tissue-Derived Mesenchymal Stem/Stromal Cells and Their Application in Acute Kidney Injury

2020 ◽  
Vol 21 (13) ◽  
pp. 4774 ◽  
Author(s):  
Jun Ho Lee ◽  
Dae Hyun Ha ◽  
Hyeon-kyu Go ◽  
Jinkwon Youn ◽  
Hyun-keun Kim ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Adipose Tissue ◽  
Stromal Cells ◽  
Large Scale ◽  
Kidney Diseases ◽  
Kidney Injury ◽  
Preclinical Studies ◽  
Scale Production ◽  
Positive Effects ◽  
Large Scale Production

Acute kidney injury (AKI) is a fatal medical episode caused by sudden kidney damage or failure, leading to the death of patients within a few hours or days. Previous studies demonstrated that exosomes derived from various mesenchymal stem/stromal cells (MSC-exosomes) have positive effects on renal injuries in multiple experimental animal models of kidney diseases including AKI. However, the mass production of exosomes is a challenge not only in preclinical studies with large animals but also for successful clinical applications. In this respect, tangential flow filtration (TFF) is suitable for good manufacturing practice (GMP)-compliant large-scale production of high-quality exosomes. Until now, no studies have been reported on the use of TFF, but rather ultracentrifugation has been almost exclusively used, to isolate exosomes for AKI therapeutic application in preclinical studies. Here, we demonstrated the reproducible large-scale production of exosomes derived from adipose tissue-derived MSC (ASC-exosomes) using TFF and the lifesaving effect of the ASC-exosomes in a lethal model of cisplatin-induced rat AKI. Our results suggest the possibility of large-scale stable production of ASC-exosomes without loss of function and their successful application in life-threatening diseases.

Urinary TCP1-eta: A Cortical Damage Marker for the Pathophysiological Diagnosis and Prognosis of Acute Kidney Injury

2019 ◽  
Vol 174 (1) ◽  
pp. 3-15 ◽  
Author(s):  
Sandra M Sancho-Martínez ◽  
Fernando Sánchez-Juanes ◽  
Víctor Blanco-Gozalo ◽  
Miguel Fontecha-Barriuso ◽  
Laura Prieto-García ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Kidney Injury ◽  
Cortical Damage ◽  
Renal Tubular Cells ◽  
Tubular Necrosis ◽  
Diagnosis And Prognosis ◽  
A Cell ◽  
Renal Tubular ◽  
Dextran Solution

Abstract Acute kidney injury (AKI) is a serious syndrome with increasing incidence and health consequences, and high mortality rate among critically ill patients. Acute kidney injury lacks a unified definition, has ambiguous semantic boundaries, and relies on defective diagnosis. This, in part, is due to the absence of biomarkers substratifying AKI patients into pathophysiological categories based on which prognosis can be assigned and clinical treatment differentiated. For instance, AKI involving acute tubular necrosis (ATN) is expected to have a worse prognosis than prerenal, purely hemodynamic AKI. However, no biomarker has been unambiguously associated with tubular cell death or is able to provide etiological distinction. We used a cell-based system to identify TCP1-eta in the culture medium as a noninvasive marker of damaged renal tubular cells. In rat models of AKI, TCP1-eta was increased in the urine co-relating with renal cortical tubule damage. When kidneys from ATN rats were perfused in situ with Krebs-dextran solution, a portion of the urinary TCP1-eta protein content excreted into urine disappeared, and another portion remained within the urine. These results indicated that TCP1-eta was secreted by tubule cells and was not fully reabsorbed by the damaged tubules, both effects contributing to the increased urinary excretion. Urinary TCP1-eta is found in many etiologically heterogeneous AKI patients, and is statistically higher in patients partially recovered from severe AKI. In conclusion, urinary TCP1-eta poses a potential, substratifying biomarker of renal cortical damage associated with bad prognosis.

scholarly journals A Regulatory miRNA–mRNA Network Is Associated with Tissue Repair Induced by Mesenchymal Stromal Cells in Acute Kidney Injury

2017 ◽  
Vol 7 ◽  
Author(s):  
Danilo Candido de Almeida ◽  
Ênio Jose Bassi ◽  
Hatylas Azevedo ◽  
Letícia Anderson ◽  
Clarice Silvia Taemi Origassa ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Mesenchymal Stromal Cells ◽  
Stromal Cells ◽  
Tissue Repair ◽  
Kidney Injury

scholarly journals Proximal tubule haptoglobin gene activation is an integral component of the acute kidney injury “stress response”

2012 ◽  
Vol 303 (1) ◽  
pp. F139-F148 ◽  
Author(s):  
Richard A. Zager ◽  
Anitha Vijayan ◽  
Ali C. M. Johnson
Keyword(s):  
Acute Kidney Injury ◽  
Proximal Tubule ◽  
Ischemia Reperfusion ◽  
Gene Activation ◽  
Kidney Injury ◽  
Normal Subjects ◽  
Gene Induction ◽  
Urine Samples ◽  
Protein Levels ◽  
Neutrophil Gelatinase

Haptoglobin (Hp) synthesis occurs almost exclusively in liver, and it is rapidly upregulated in response to stress. Because many of the pathways that initiate hepatic Hp synthesis are also operative during acute kidney injury (AKI), we tested whether AKI activates the renal cortical Hp gene. CD-1 mice were subjected to six diverse AKI models: ischemia-reperfusion, glycerol injection, cisplatin nephrotoxicity, myoglobinuria, endotoxemia, and bilateral ureteral obstruction. Renal cortical Hp gene induction was determined either 4–72 h or 1–3 wk later by measuring Hp mRNA and protein levels. Relative renal vs. hepatic Hp gene induction during endotoxemia was also assessed. Each form of AKI induced striking and sustained Hp mRNA increases, leading to ∼10- to 100-fold renal Hp protein elevations (ELISA; Western blot). Immunohistochemistry, and isolated proximal tubule assessments, indicated that the proximal tubule was the dominant (if not only) site of the renal Hp increases. Corresponding urinary and plasma Hp elevations were surrogate markers of this response. Endotoxemia evoked 25-fold greater Hp mRNA increases in kidney vs. liver, indicating marked renal Hp gene reactivity. Clinical relevance of these findings was suggested by observations that urine samples from 16 patients with established AKI had statistically higher (∼12×) urinary Hp levels than urine samples from either normal subjects or from 15 patients with chronic kidney disease. These AKI-associated urinary Hp increases mirrored those seen for urinary neutrophil gelatinase-associated lipoprotein, a well accepted AKI biomarker gene. In summary, these studies provide the first evidence that AKI evokes rapid, marked, and sustained induction of the proximal tubule Hp gene. Hp's known antioxidant, as well as its protean pro- and anti-inflammatory, actions imply potentially diverse effects on the evolution of acute tubular injury.

scholarly journals Human umbilical cord-derived mesenchymal stromal cells protect against premature renal senescence resulting from oxidative stress in rats with acute kidney injury

2017 ◽  
Vol 8 (1) ◽  
Author(s):  
Camila Eleuterio Rodrigues ◽  
José Manuel Condor Capcha ◽  
Ana Carolina de Bragança ◽  
Talita Rojas Sanches ◽  
Priscila Queiroz Gouveia ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Acute Kidney Injury ◽  
Umbilical Cord ◽  
Mesenchymal Stromal Cells ◽  
Stromal Cells ◽  
Kidney Injury ◽  
Human Umbilical Cord ◽  
Renal Senescence

scholarly journals Urinary Metabolome Analyses of Patients with Acute Kidney Injury Using Capillary Electrophoresis-Mass Spectrometry

Metabolites ◽  
2021 ◽  
Vol 11 (10) ◽  
pp. 671
Author(s):  
Rintaro Saito ◽  
Akiyoshi Hirayama ◽  
Arisa Akiba ◽  
Yushi Kamei ◽  
Yuyu Kato ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Acute Kidney Injury ◽  
Capillary Electrophoresis ◽  
Kidney Injury ◽  
Urine Samples ◽  
Rapid Decline ◽  
Time Points ◽  
Flight Mass Spectrometry ◽  
Best Value ◽  
Time Point

Acute kidney injury (AKI) is defined as a rapid decline in kidney function. The associated syndromes may lead to increased morbidity and mortality, but its early detection remains difficult. Using capillary electrophoresis time-of-flight mass spectrometry (CE-TOFMS), we analyzed the urinary metabolomic profile of patients admitted to the intensive care unit (ICU) after invasive surgery. Urine samples were collected at six time points: before surgery, at ICU admission and 6, 12, 24 and 48 h after. First, urine samples from 61 initial patients (non-AKI: 23, mild AKI: 24, severe AKI: 14) were measured, followed by the measurement of urine samples from 60 additional patients (non-AKI: 40, mild AKI: 20). Glycine and ethanolamine were decreased in patients with AKI compared with non-AKI patients at 6–24 h in the two groups. The linear statistical model constructed at each time point by machine learning achieved the best performance at 24 h (median AUC: 89%, cross-validated) for the 1st group. When cross-validated between the two groups, the AUC showed the best value of 70% at 12 h. These results identified metabolites and time points that show patterns specific to subjects who develop AKI, paving the way for the development of better biomarkers.

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