Transcriptomic Signatures of Exacerbated Progression in Leptospirosis Subclinical Chronic Kidney Disease with Secondary Nephrotoxic Injury

2021 ◽  
Author(s):  
Li-Fang Chou ◽  
TingWen Chen ◽  
Huan-Yu Yang ◽  
Ya-Chung Tian ◽  
Ming-Yang Chang ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Topoisomerase Ii ◽  
Low Dose ◽  
Expression Patterns ◽  
Kidney Injury ◽  
Differentially Expressed ◽  
High Dose ◽  
Integrin Linked Kinase ◽  
Topoisomerase Ii Α

High-incidence regions of Leptospirosis caused by Leptospira spp., coincide with chronic kidney disease. This study investigates whether asymptomatic leptospirosis is an emerging culprit that predispose to progressive chronic kidney disease when superimposed on secondary nephrotoxic injury. Kidney histology/function and whole-transcriptomic profiles were evaluated for leptospira-infected C57/BL6 mice with adenine-induced kidney injury. The extent of tubulointerstitial kidney lesions and the expression of inflammation/fibrosis genes in infected mice with low-dose (0.1%) adenine, particularly in high-dose (0.2%) adenine-fed superimposed on leptospira-infected mice, were significantly increased compared with mice following infection or adenine diet alone and the findings are consistent with renal transcriptome analysis. Pathway enrichment findings showed integrin β- and fibronectin-encoding genes had distinct expression within the integrin-linked kinase signaling pathway which were up-regulated in 0.2% adenine-fed leptospira-infected mice but not in 0.2% adenine-fed mice, indicating background subclinical leptospiral infection indeed enhanced subsequent secondary nephrotoxic kidney injury and potential pathogenic molecules associated with secondary nephrotoxic leptospirosis. Comparative analysis of gene-expression patterns with UUO-induced mouse renal fibrosis and patients with chronic kidney disease showed that differentially expressed orthologous genes such as hemoglobin α, PDZ binding kinase and DNA topoisomerase II α were identified in infected mice fed with low-dose and high-dose adenine, respectively, revealing differentially expressed signatures identical to those found in the datasets and may serve as markers of aggravated kidney progression. This study indicates that background subclinical leptospirosis, when subjected to various degrees of subsequent secondary nephrotoxic injury, may predispose to exacerbated fibrosis, mimicking the pathophysiological process of progressive chronic kidney disease.

scholarly journals Cyclophilin D Promotes Acute, but Not Chronic, Kidney Injury in a Mouse Model of Aristolochic Acid Toxicity

Toxins ◽  
2021 ◽  
Vol 13 (10) ◽  
pp. 700
Author(s):  
Khai Gene Leong ◽  
Elyce Ozols ◽  
John Kanellis ◽  
Frank Y. Ma ◽  
David J. Nikolic-Paterson
Keyword(s):  
Chronic Kidney Disease ◽  
Acute Kidney Injury ◽  
Cell Death ◽  
Kidney Disease ◽  
Low Dose ◽  
Aristolochic Acid ◽  
Chinese Herb ◽  
Kidney Injury ◽  
High Dose ◽  
Cyclophilin D

The plant-derived toxin, aristolochic acid (AA), is the cause of Chinese Herb Nephropathy and Balkan Nephropathy. Ingestion of high dose AA induces acute kidney injury, while chronic low dose ingestion leads to progressive kidney disease. Ingested AA is taken up by tubular epithelial cells of the kidney, leading to DNA damage and cell death. Cyclophilin D (CypD) participates in mitochondrial-dependent cell death, but whether this mechanism operates in acute or chronic AA-induced kidney injury is unknown. We addressed this question by exposing CypD-/- and wild type (WT) mice to acute high dose, or chronic low dose, AA. Administration of 5 mg/kg AA to WT mice induced acute kidney injury 3 days later, characterised by loss of kidney function, tubular cell damage and death, and neutrophil infiltration. All of these parameters were significantly reduced in CypD-/- mice. Chronic low dose (2 mg/kg AA) administration in WT mice resulted in chronic kidney disease with impaired renal function and renal fibrosis by day 28. However, CypD-/- mice were not protected from AA-induced chronic kidney disease. In conclusion, CypD facilitates AA-induced acute kidney damage, but CypD does not contribute to the transition of acute kidney injury to chronic kidney disease during ongoing AA exposure.

scholarly journals Low-dose hydralazine prevents fibrosis in a murine model of acute kidney injury–to–chronic kidney disease progression

2017 ◽  
Vol 91 (1) ◽  
pp. 157-176 ◽  
Author(s):  
Björn Tampe ◽  
Ulrike Steinle ◽  
Désirée Tampe ◽  
Julienne L. Carstens ◽  
Peter Korsten ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Acute Kidney Injury ◽  
Kidney Disease ◽  
Disease Progression ◽  
Murine Model ◽  
Low Dose ◽  
Kidney Injury ◽  
Chronic Kidney Disease Progression ◽  
Kidney Disease Progression

scholarly journals Repeated administration of low-dose cisplatin in mice induces fibrosis

2016 ◽  
Vol 310 (6) ◽  
pp. F560-F568 ◽  
Author(s):  
Cierra N. Sharp ◽  
Mark A. Doll ◽  
Tess V. Dupre ◽  
Parag P. Shah ◽  
Marimuthu Subathra ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Transforming Growth Factor ◽  
Interstitial Fibrosis ◽  
Smooth Muscle Actin ◽  
Kidney Injury ◽  
High Dose ◽  
Long Term Study ◽  
Increased Risk ◽  
Repeated Dosing

Cisplatin, a chemotherapeutic used for the treatment of solid cancers, has nephrotoxic side effects leading to acute kidney injury (AKI). Cisplatin cannot be given to patients that have comorbidities that predispose them to an increased risk for AKI. Even without these comorbidities, 30% of patients administered cisplatin will develop kidney injury, requiring the oncologist to withhold or reduce the next dose, leading to a less effective therapeutic regimen. Although recovery can occur after one episode of cisplatin-induced AKI, longitudinal studies have indicated that multiple episodes of AKI lead to the development of chronic kidney disease, an irreversible disease with no current treatment. The standard mouse model of cisplatin-induced AKI consists of one high dose of cisplatin (>20 mg/kg) that is lethal to the animal 3 days later. This model does not accurately reflect the dosing regimen patients receive nor does it allow for the long-term study of kidney function and biology. We have developed a repeated dosing model whereby cisplatin is given once a week for 4 wk. Comparison of the repeated dosing model with the standard dosing model demonstrated that inflammatory cytokines and chemokines were induced in the repeated dosing model, but levels of cell death were lower in the repeated dosing model. The repeated dosing model had increased levels of fibrotic markers (fibronectin, transforming growth factor-β, and α-smooth muscle actin) and interstitial fibrosis. These data indicate that the repeated dosing model can be used to study the AKI to chronic kidney disease progression as well as the mechanisms of this progression.

High Dose of N-Acetylcystein Prevents Acute Kidney Injury in Chronic Kidney Disease Patients Undergoing Myocardial Revascularization

2014 ◽  
Vol 97 (5) ◽  
pp. 1617-1623 ◽  
Author(s):  
Eduesley Santana-Santos ◽  
Luis Henrique W. Gowdak ◽  
Fabio A. Gaiotto ◽  
Luiz B. Puig ◽  
Ludhmila A. Hajjar ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Acute Kidney Injury ◽  
Kidney Disease ◽  
Myocardial Revascularization ◽  
Kidney Injury ◽  
High Dose

scholarly journals Cisplatin Effects in Lung Adenocarcinoma-bearing Mice, Alone and in Combination with Erlotinib

2018 ◽  
Vol 46 (8) ◽  
pp. 1049-1050
Author(s):  
Cierra N. Sharp
Keyword(s):  
Chronic Kidney Disease ◽  
Acute Kidney Injury ◽  
Kidney Disease ◽  
Mouse Model ◽  
Lung Adenocarcinoma ◽  
Dose Regimen ◽  
Low Dose ◽  
Kidney Injury ◽  
Transgenic Mouse Model ◽  
Cisplatin Nephrotoxicity

Cisplatin causes nephrotoxicity that can lead to the development of acute kidney injury or chronic kidney disease. However, the current mouse model of cisplatin nephrotoxicity is neither physiologically nor clinically relevant. Our goal was to improve upon these deficits by developing a repeated, low-dose regimen of cisplatin and combining it with a transgenic mouse model of lung adenocarcinoma. This overview details how addressing these deficits have improved our understanding of cisplatin-induced kidney injury.

scholarly journals Administration of metformin in type 2 diabetes mellitus patients with chronic kidney disease; facts and myths

2019 ◽  
Vol 9 (1) ◽  
pp. e04-e04
Author(s):  
Mohsen Akhavan Sepahi ◽  
Bhaskar VKS Lakkakula ◽  
Steven James Kellner ◽  
Rohollah Valizadeh
Keyword(s):  
Diabetes Mellitus ◽  
Type 2 Diabetes ◽  
Chronic Kidney Disease ◽  
Type 2 Diabetes Mellitus ◽  
Kidney Disease ◽  
Adverse Effects ◽  
Randomized Trials ◽  
Low Dose ◽  
Kidney Injury

There are few publications reporting adverse effects of metformin for patients with type 2 diabetes mellitus (T2DM) and chronic kidney disease (CKD). Although some of these reports have made big claims about the adverse effects of metformin in patients with renal failure, the majority of studies showed a superior safety profile for metformin compared with other antidiabetic medications in these patients. Further, metformin use is not contributing to an increased incidence of acute kidney injury (AKI). In conclusion, we suggest that a low dose of metformin is safe to use in patients with or without CKD. Multicenter randomized trials are required to further discover the benefits of the risk of metformin therapy in different stages of CKD and its effect on progression of CKD.

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