The Immunomodulatory Effect of the Gut Microbiota in Kidney Disease

The human gut microbiota is a complex cluster composed of 100 trillion microorganisms, which holds a symbiotic relationship with the host under normal circumstances. Intestinal flora can facilitate the treatment of human metabolic dysfunctions and interact with the intestinal tract, which could influence intestinal tolerance, immunity, and sensitivity to inflammation. In recent years, significant interests have evolved on the association of intestinal microbiota and kidney diseases within the academic circle. Abnormal changes in intestinal microbiota, known as dysbiosis, can affect the integrity of the intestinal barrier, resulting in the bacterial translocation, production, and accumulation of dysbiotic gut-derived metabolites, such as urea, indoxyl sulfate (IS), and p-cresyl sulfate (PCS). These processes lead to the abnormal activation of immune cells; overproduction of antibodies, immune complexes, and inflammatory factors; and inflammatory cell infiltration that can directly or indirectly cause damage to the renal parenchyma. The aim of this review is to summarize the role of intestinal flora in the development and progression of several renal diseases, such as lupus nephritis, chronic kidney disease, diabetic nephropathy, and renal ischemia-reperfusion injury. Further research on these mechanisms should provide insights into the therapeutic potential of regulating intestinal flora and intervening related molecular targets for the abovementioned nephropathy.

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A Link between Chronic Kidney Disease and Gut Microbiota in Immunological and Nutritional Aspects

Nutrients ◽

10.3390/nu13103637 ◽

2021 ◽

Vol 13 (10) ◽

pp. 3637

Author(s):

Paulina Mertowska ◽

Sebastian Mertowski ◽

Julia Wojnicka ◽

Izabela Korona-Głowniak ◽

Ewelina Grywalska ◽

...

Keyword(s):

Chronic Kidney Disease ◽

Immune System ◽

Kidney Disease ◽

Gut Microbiota ◽

Intestinal Microbiota ◽

Kidney Diseases ◽

Disease Onset ◽

Kidney Injury ◽

Dietary Factors

Chronic kidney disease (CKD) is generally progressive and irreversible, structural or functional renal impairment for 3 or more months affecting multiple metabolic pathways. Recently, the composition, dynamics, and stability of a patient’s microbiota has been noted to play a significant role during disease onset or progression. Increasing urea concentration during CKD can lead to an acceleration of the process of kidney injury leading to alterations in the intestinal microbiota that can increase the production of gut-derived toxins and alter the intestinal epithelial barrier. A detailed analysis of the relationship between the role of intestinal microbiota and the development of inflammation within the symbiotic and dysbiotic intestinal microbiota showed significant changes in kidney dysfunction. Several recent studies have determined that dietary factors can significantly influence the activation of immune cells and their mediators. Moreover, dietary changes can profoundly affect the balance of gut microbiota. The aim of this review is to present the importance and factors influencing the differentiation of the human microbiota in the progression of kidney diseases, such as CKD, IgA nephropathy, idiopatic nephropathy, and diabetic kidney disease, with particular emphasis on the role of the immune system. Moreover, the effects of nutrients, bioactive compounds on the immune system in development of chronic kidney disease were reviewed.

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Renal redox dysregulation in AKI: application for oxidative stress marker of AKI

AJP Renal Physiology ◽

10.1152/ajprenal.00381.2013 ◽

2014 ◽

Vol 307 (12) ◽

pp. F1342-F1351 ◽

Cited By ~ 17

Author(s):

Kenji Kasuno ◽

Kiichi Shirakawa ◽

Haruyoshi Yoshida ◽

Kiyoshi Mori ◽

Hideki Kimura ◽

...

Keyword(s):

Oxidative Stress ◽

Chronic Kidney Disease ◽

Kidney Disease ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Characteristic Curve ◽

Regulatory Protein ◽

Redox System ◽

Oxidative Stress Marker ◽

Renal Diseases

Oxidative stress is a major determinant of acute kidney injury (AKI); however, the effects of an AKI on renal redox system are unclear, and few existing AKI markers are suitable for evaluating oxidative stress. We measured urinary levels of the redox-regulatory protein thioredoxin 1 (TRX1) in patients with various kinds of kidney disease and in mice with renal ischemia-reperfusion injury. Urinary TRX1 levels were markedly higher in patients with AKI than in those with chronic kidney disease or in healthy subjects. In a receiver operating characteristic curve analysis to differentiate between AKI and other renal diseases, the area under the curve for urinary TRX1 was 0.94 (95% confidence interval, 0.90–0.98), and the sensitivity and specificity were 0.88 and 0.88, respectively, at the optimal cutoff value of 43.0 μg/g creatinine. Immunostaining revealed TRX1 to be diffusely distributed in the tubules of normal kidneys, but to be shifted to the brush borders or urinary lumen in injured tubules in both mice and humans with AKI. Urinary TRX1 in AKI was predominantly in the oxidized form. In cultured human proximal tubular epithelial cells, hydrogen peroxide specifically and dose dependently increased TRX1 levels in the culture supernatant, while reducing intracellular levels. These findings suggest that urinary TRX1 is an oxidative stress-specific biomarker useful for distinguishing AKI from chronic kidney disease and healthy kidneys.

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D-Serine, an emerging biomarker of kidney diseases, is a hidden substrate of sodium-coupled monocarboxylate transporters

10.1101/2020.08.10.244822 ◽

2020 ◽

Cited By ~ 1

Author(s):

Pattama Wiriyasermkul ◽

Satomi Moriyama ◽

Yoko Tanaka ◽

Pornparn Kongpracha ◽

Nodoka Nakamae ◽

...

Keyword(s):

Membrane Transport ◽

Ischemia Reperfusion Injury ◽

Kidney Diseases ◽

Ischemia Reperfusion ◽

Monocarboxylate Transporter ◽

Transport Systems ◽

Monocarboxylate Transporters ◽

Renal Diseases ◽

Delay In Diagnosis ◽

Depth Analysis

AbstractDelay in diagnosis of renal injury has profound impacts on morbidity and mortality. Damage of proximal tubules by the injury impairs not only individual membrane transport proteins but also coordinated transport systems. In this study, we analyzed the proteome of apical membranes of proximal tubular epithelium from the mouse kidney with early ischemia-reperfusion injury (IRI), a well-known acute kidney injury (AKI) model. The proteome showed drastic elevations of the injury-responsive proteins and depressions of abundant transporters, leading to the prediction of biomarkers for early IRI. As the benchmark of our in-depth analysis from the proteome, we characterized transporters for D-serine, a promising renal diseases’ biomarker. Using cell-based and cell-free methods, we identified sodium-coupled monocarboxylate transporters (SMCTs) as the D-serine transporters. This finding enlightens the role of non-canonical substrate transport and clarifies the D-serine transport systems in the kidney. Our approaches can be applied for investigation of other membrane transport systems.Impact statementProteomics and biochemical analysis reveal D-serine as a non-canonical substrate of sodium-coupled monocarboxylate transporter SMCTs

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Therapeutic potential of endothelin receptor antagonism in kidney disease

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00478.2015 ◽

2016 ◽

Vol 310 (5) ◽

pp. R388-R397 ◽

Cited By ~ 9

Author(s):

Alicja Czopek ◽

Rebecca Moorhouse ◽

David J. Webb ◽

Neeraj Dhaun

Keyword(s):

Chronic Kidney Disease ◽

Kidney Disease ◽

Renal Disease ◽

Clinical Studies ◽

Ischemia Reperfusion Injury ◽

Therapeutic Potential ◽

Ischemia Reperfusion ◽

Renal Physiology ◽

Receptor Antagonists ◽

Receptor Antagonism

Our growing understanding of the role of the endothelin (ET) system in renal physiology and pathophysiology is from emerging studies of renal disease in animal models and humans. ET receptor antagonists reduce blood pressure and proteinuria in chronic kidney disease and cause regression of renal injury in animals. However, the therapeutic potential of ET receptor antagonism has not been fully explored and clinical studies have been largely limited to patients with diabetic nephropathy. There remains a need for more work in nondiabetic chronic kidney disease, end-stage renal disease (patients requiring maintenance dialysis and those with a functioning kidney transplant), ischemia reperfusion injury, and sickle cell disease. The current review summarizes the most recent advances in both preclinical and clinical studies of ET receptor antagonists in the field of kidney disease.

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Monocytic MDSC mobilization promotes tumor recurrence after liver transplantation via CXCL10/TLR4/MMP14 signaling

Cell Death and Disease ◽

10.1038/s41419-021-03788-4 ◽

2021 ◽

Vol 12 (5) ◽

Author(s):

Hui Liu ◽

Chang Chun Ling ◽

Wai Ho Oscar Yeung ◽

Li Pang ◽

Jiang Liu ◽

...

Keyword(s):

Liver Transplantation ◽

Tumor Recurrence ◽

Ischemia Reperfusion Injury ◽

Therapeutic Potential ◽

Ischemia Reperfusion ◽

Weight Ratio ◽

Liver Graft ◽

Mouse Tumor ◽

Hepatic Ischemia ◽

Tlr4 Signaling

AbstractTumor recurrence is the major obstacle for pushing the envelope of liver transplantation for hepatocellular carcinoma (HCC) patients. The inflammatory cascades activated by acute liver graft injury promote tumor recurrence. We aimed to explore the role and mechanism of myeloid-derived suppressor cell (MDSC) mobilization induced by liver graft injury on tumor recurrence. By analyzing 331 HCC patients who received liver transplantation, the patients with graft weight ratio (GWR, the weight of liver graft divided by the estimated standard liver weight of recipient) <60% had higher tumor recurrence than GWR ≥60% ones. MDSCs and CXCL10/TLR4 levels were significantly increased in patients with GWR <60% or tumor recurrence. These findings were further validated in our rat orthotopic liver transplantation model. In CXCL10−/− and TLR4−/− mice of hepatic ischemia/reperfusion injury plus major hepatectomy (IRH) model, monocytic MDSCs, instead of granulocytic MDSCs, were significantly decreased. Importantly, CXCL10 deficiency reduced the accumulation of TLR4+ monocytic MDSCs, and CXCL10 increased MDSC mobilization in the presence of TLR4. Moreover, MMP14 was identified as the key molecule bridging CXCL10/TLR4 signaling and MDSC mobilization. Knockout or inhibition of CXCL10/TLR4 signaling significantly reduced the tumor growth with decreased monocytic MDSCs and MMP14 in the mouse tumor recurrent model. Our data indicated that monocytic MDSCs were mobilized and recruited to liver graft during acute phase injury, and to promote HCC recurrence after transplantation. Targeting MDSC mobilization via CXCL10/TLR4/MMP14 signaling may represent the therapeutic potential in decreasing post-transplant liver tumor recurrence.

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Role of lung and gut microbiota on lung cancer pathogenesis

Journal of Cancer Research and Clinical Oncology ◽

10.1007/s00432-021-03644-0 ◽

2021 ◽

Author(s):

Yue Zhao ◽

Yuxia Liu ◽

Shuang Li ◽

Zhaoyun Peng ◽

Xiantao Liu ◽

...

Keyword(s):

Lung Cancer ◽

Gut Microbiota ◽

Cancer Progression ◽

Gut Microbiome ◽

Intestinal Flora ◽

Inflammatory Factors ◽

Cancer Pathogenesis ◽

Research Findings ◽

Relationship Of

Abstract Background Lung cancer is the leading cause of cancer-related deaths worldwide (Ferlay et al., Int J Cancer 136:E359–386, 2015). In addition, lung cancer is associated with the highest mortality among all cancer types (Wu et al., Exp Ther Med 16:3004–3010, 2018). Previous studies report that microbiota play an important role in lung cancer. Notably, changes in lung and gut microbiota, are associated with progression of lung cancer. Several studies report that lung and gut microbiome promote lung cancer initiation and development by modulating metabolic pathways, inhibiting the function of immune cells, and producing pro-inflammatory factors. In addition, some factors such as microbiota dysbiosis, affect production of bacteriotoxins, genotoxicity and virulence effect, therefore, they play a key role in cancer progression. These findings imply that lung and gut microbiome are potential markers and targets for lung cancer. However, the role of microbiota in development and progression of lung cancer has not been fully explored. Purpose The aim of this study was to systemically review recent research findings on relationship of lung and gut microbiota with lung cancer. In addition, we explored gut–lung axis and potential mechanisms of lung and gut microbiota in modulating lung cancer progression. Conclusion Pulmonary and intestinal flora influence the occurrence, development, treatment and prognosis of lung cancer, and will provide novel strategies for prevention, diagnosis, and treatment of lung cancer.

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Propofol attenuates lung ischemia/reperfusion injury though the involvement of the MALAT1/microRNA-144/GSK3β axis

Molecular Medicine ◽

10.1186/s10020-021-00332-0 ◽

2021 ◽

Vol 27 (1) ◽

Author(s):

Jian-Ping Zhang ◽

Wei-Jing Zhang ◽

Miao Yang ◽

Hua Fang

Keyword(s):

Cell Apoptosis ◽

Ischemia Reperfusion Injury ◽

Glycogen Synthase ◽

Ischemia Reperfusion ◽

Inflammatory Factors ◽

Therapeutic Effects ◽

Protective Effects ◽

Loss Of Function

Abstract Background Propofol, an intravenous anesthetic, was proven to protect against lung ischemia/reperfusion (I/R) injury. However, the detailed mechanism of Propofol in lung I/R injury is still elusive. This study was designed to explore the therapeutic effects of Propofol, both in vivo and in vitro, on lung I/R injury and the underlying mechanisms related to metastasis-associated lung adenocarcinoma transcript 1 (MALAT1)/microRNA-144 (miR-144)/glycogen synthase kinase-3β (GSK3β). Methods C57BL/6 mice were used to establish a lung I/R injury model while pulmonary microvascular endothelial cells (PMVECs) were constructed as hypoxia/reperfusion (H/R) cellular model, both of which were performed with Propofol treatment. Gain- or loss-of-function approaches were subsequently employed, followed by observation of cell apoptosis in lung tissues and evaluation of proliferative and apoptotic capabilities in H/R cells. Meanwhile, the inflammatory factors, autophagosomes, and autophagy-related proteins were measured. Results Our experimental data revealed that Propofol treatment could decrease the elevated expression of MALAT1 following I/R injury or H/R induction, indicating its protection against lung I/R injury. Additionally, overexpressing MALAT1 or GSK3β promoted the activation of autophagosomes, proinflammatory factor release, and cell apoptosis, suggesting that overexpressing MALAT1 or GSK3β may reverse the protective effects of Propofol against lung I/R injury. MALAT1 was identified to negatively regulate miR-144 to upregulate the GSK3β expression. Conclusion Overall, our study demonstrated that Propofol played a protective role in lung I/R injury by suppressing autophagy and decreasing release of inflammatory factors, with the possible involvement of the MALAT1/miR-144/GSK3β axis.

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IP3R1 regulates Ca2+ transport and pyroptosis through the NLRP3/Caspase-1 pathway in myocardial ischemia/reperfusion injury

Cell Death Discovery ◽

10.1038/s41420-021-00404-4 ◽

2021 ◽

Vol 7 (1) ◽

Author(s):

Guixi Mo ◽

Xin Liu ◽

Yiyue Zhong ◽

Jian Mo ◽

Zhiyi Li ◽

...

Keyword(s):

Myocardial Ischemia ◽

Ischemia Reperfusion Injury ◽

Cell Model ◽

Ischemia Reperfusion ◽

Inflammatory Factors ◽

Rat Cardiomyocytes ◽

Adult Rat ◽

Caspase 1 ◽

Intracellular Ca ◽

Myocardial Ischemia Reperfusion

AbstractIntracellular ion channel inositol 1,4,5-triphosphate receptor (IP3R1) releases Ca2+ from endoplasmic reticulum. The disturbance of IP3R1 is related to several neurodegenerative diseases. This study investigated the mechanism of IP3R1 in myocardial ischemia/reperfusion (MI/R). After MI/R modeling, IP3R1 expression was silenced in myocardium of MI/R rats to explore its role in the concentration of myocardial enzymes, infarct area, Ca2+ level, NLRP3/Caspase-1, and pyroptosis markers and inflammatory factors. The adult rat cardiomyocytes were isolated and cultured to establish hypoxia/reperfusion (H/R) cell model. The expression of IP3R1 was downregulated or ERP44 was overexpressed in H/R-induced cells. Nifedipine D6 was added to H/R-induced cells to block Ca2+ channel or Nigericin was added to activate NLRP3. IP3R1 was highly expressed in myocardium of MI/R rats, and silencing IP3R1 alleviated MI/R injury, reduced Ca2+ overload, inflammation and pyroptosis in MI/R rats, and H/R-induced cells. The binding of ERP44 to IP3R1 inhibited Ca2+ overload, alleviated cardiomyocyte inflammation, and pyroptosis. The increase of intracellular Ca2+ level caused H/R-induced cardiomyocyte pyroptosis through the NLRP3/Caspase-1 pathway. Activation of NLRP3 pathway reversed the protection of IP3R1 inhibition/ERP44 overexpression/Nifedipine D6 on H/R-induced cells. Overall, ERP44 binding to IP3R1 inhibits Ca2+ overload, thus alleviating pyroptosis and MI/R injury.

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Beyond a Passive Conduit: Implications of Lymphatic Biology for Kidney Diseases

Journal of the American Society of Nephrology ◽

10.1681/asn.2019121320 ◽

2020 ◽

Vol 31 (6) ◽

pp. 1178-1190 ◽

Cited By ~ 3

Author(s):

Daniyal J. Jafree ◽

David A. Long

Keyword(s):

Kidney Disease ◽

Therapeutic Potential ◽

Kidney Diseases ◽

Transplant Rejection ◽

Lymphatic Vessels ◽

Renal Physiology ◽

Clear Fluid ◽

Adult Kidney ◽

And Function ◽

Development Structure

The kidney contains a network of lymphatic vessels that clear fluid, small molecules, and cells from the renal interstitium. Through modulating immune responses and via crosstalk with surrounding renal cells, lymphatic vessels have been implicated in the progression and maintenance of kidney disease. In this Review, we provide an overview of the development, structure, and function of lymphatic vessels in the healthy adult kidney. We then highlight the contributions of lymphatic vessels to multiple forms of renal pathology, emphasizing CKD, transplant rejection, and polycystic kidney disease and discuss strategies to target renal lymphatics using genetic and pharmacologic approaches. Overall, we argue the case for lymphatics playing a fundamental role in renal physiology and pathology and treatments modulating these vessels having therapeutic potential across the spectrum of kidney disease.

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