scholarly journals CPT1α maintains phenotype of tubules via mitochondrial respiration during kidney injury and repair

2021 ◽  
Vol 12 (8) ◽  
Author(s):  
Qi Yuan ◽  
Yunhui Lv ◽  
Hao Ding ◽  
Qingqing Ke ◽  
Caifeng Shi ◽  
...  
Keyword(s):  
Folic Acid ◽  
Mitochondrial Respiration ◽  
Interstitial Fibrosis ◽  
Kidney Diseases ◽  
Cell Damage ◽  
Kidney Injury ◽  
Atp Production ◽  
Genetic Ablation ◽  
Proximal Tubular ◽  
Injury And Repair

AbstractImpaired energy metabolism in proximal tubular epithelial cells (PTECs) is strongly associated with various kidney diseases. Here, we characterized proximal tubular phenotype alternations during kidney injury and repair in a mouse model of folic acid nephropathy, in parallel, identified carnitine palmitoyltransferase 1α (CPT1α) as an energy stress response accompanied by renal tubular dedifferentiation. Genetic ablation of Cpt1α aggravated the tubular injury and interstitial fibrosis and hampered kidney repair indicate that CPT1α is vital for the preservation and recovery of tubular phenotype. Our data showed that the lipid accumulation and mitochondrial mass reduction induced by folic acid were persistent and became progressively more severe in PTECs without CPT1α. Interference of CPT1α reduced capacities of mitochondrial respiration and ATP production in PTECs, and further sensitized cells to folic acid-induced phenotypic changes. On the contrary, overexpression of CPT1α protected mitochondrial respiration and prevented against folic acid-induced tubular cell damage. These findings link CPT1α to intrinsic mechanisms regulating the mitochondrial respiration and phenotype of kidney tubules that may contribute to renal pathology during injury and repair.

scholarly journals Janus-Faced: Molecular Mechanisms and Versatile Nature of Renal Fibrosis

Kidney360 ◽  
2020 ◽  
Vol 1 (7) ◽  
pp. 697-704
Author(s):  
Hiroyuki Arai ◽  
Motoko Yanagita
Keyword(s):  
Renal Fibrosis ◽  
Molecular Mechanisms ◽  
Kidney Diseases ◽  
Kidney Injury ◽  
Lymphoid Tissues ◽  
Functional Heterogeneity ◽  
Current Perspective ◽  
Proximal Tubular ◽  
Kidney Disease Progression ◽  
Injury And Repair

Renal fibrosis is a major hallmark of CKD, regardless of the underlying etiology. In fibrosis development and progression, myofibroblasts play a pivotal role, producing extracellular matrix and interacting with various resident cells in the kidney. Over the past decade, the origin of myofibroblasts has been thoroughly investigated. Emerging evidence suggests that renal myofibroblasts originate from several cellular sources, including resident fibroblasts, pericytes, and bone marrow–derived cells. The contribution of resident fibroblasts is most crucial, and currently available data strongly suggest the importance of functional heterogeneity and plasticity of fibroblasts in kidney disease progression. Resident fibroblasts acquire distinct phenotypes based on their local microenvironment and exert multifactorial functions. For example, age-dependent alterations of renal fibroblasts make a significant contribution to the formation of tertiary lymphoid tissues, which promote local inflammation after injury in the aged kidney. In conjunction with fibrosis development, dysfunction of resident fibroblasts provokes unique pathologic conditions including renal anemia and peritubular capillary loss, both of which are major complications of CKD. Although renal fibrosis is considered detrimental in general, recent studies suggest it has beneficial roles, such as maintaining functional crosstalk with injured proximal tubular cells and supporting their regeneration. These findings provide novel insight into the mechanisms of renal fibrosis, which could be regarded as an adaptive process of kidney injury and repair. Precise understanding of the functional heterogeneity of resident fibroblasts and myofibroblasts has the potential to facilitate the development of novel therapeutics against kidney diseases. In this review, we describe the current perspective on the origin of myofibroblasts and fibroblast heterogeneity, with special emphasis on the dual aspects of renal fibrosis, both beneficial and detrimental, in CKD progression.

scholarly journals Nephrotoxicity Of Polymyxin B: Experimental Study In Cells And Implications For Nursing Practice

2014 ◽  
Vol 48 (2) ◽  
pp. 272-277 ◽  
Author(s):  
Luciana Barros de Moura Neiva ◽  
Fernanda Teixeira Borges ◽  
Mirian Watanabe ◽  
Edson de Andrade Pessoa ◽  
Dulce Aparecida Barbosa ◽  
...  
Keyword(s):  
Fluorescent Dyes ◽  
Cell Damage ◽  
Kidney Injury ◽  
In Vitro Study ◽  
Polymyxin B ◽  
Concentration Cell ◽  
Tubular Cells ◽  
Risk Patients ◽  
Proximal Tubular

The aim of the study was to characterize the cell damage mechanisms involved in the pathophysiology of cytotoxicity of polymyxin B in proximal tubular cells (LLC - PK1) and discuss about the nurses interventions to identify at risk patients and consider prevention or treatment of nephrotoxicity acute kidney injury. This is a quantitative experimental in vitro study, in which the cells were exposed to 375μM polymyxin B sulfate concentration. Cell viability was determined by exclusion of fluorescent dyes and morphological method with visualization of apoptotic bodies for fluorescence microscopy. Cells exposed to polymyxin B showed reduced viability, increased number of apoptotic cells and a higher concentration of the enzyme lactate dehydrogenase. The administration of polymyxin B in vitro showed the need for actions to minimize adverse effects such as nephrotoxicity.


scholarly journals Proximal tubule-specific overexpression of netrin-1 suppresses acute kidney injury-induced interstitial fibrosis and glomerulosclerosis through suppression of IL-6/STAT3 signaling

2013 ◽  
Vol 304 (8) ◽  
pp. F1054-F1065 ◽  
Author(s):  
Punithavathi Ranganathan ◽  
Calpurnia Jayakumar ◽  
Ganesan Ramesh
Keyword(s):  
Acute Kidney Injury ◽  
Epithelial Cells ◽  
Interstitial Fibrosis ◽  
Kidney Injury ◽  
Transgenic Animals ◽  
Acute Injury ◽  
Tubular Epithelial Cells ◽  
Wild Type ◽  
Proximal Tubular Epithelial Cells ◽  
Proximal Tubular

Acute kidney injury-induced organ fibrosis is recognized as a major risk factor for the development of chronic kidney disease, which remains one of the leading causes of death in the developed world. However, knowledge on molecules that may suppress the fibrogenic response after injury is lacking. In ischemic models of acute kidney injury, we demonstrate a new function of netrin-1 in regulating interstitial fibrosis. Acute injury was promptly followed by a rise in serum creatinine in both wild-type and netrin-1 transgenic animals. However, the wild-type showed a slow recovery of kidney function compared with netrin-1 transgenic animals and reached baseline by 3 wk. Histological examination showed increased infiltration of interstitial macrophages, extensive fibrosis, reduction of capillary density, and glomerulosclerosis. Collagen IV and α-smooth muscle actin expression was absent in sham-operated kidneys; however, their expression was significantly increased at 2 wk and peaked at 3 wk after reperfusion. These changes were reduced in the transgenic mouse kidney, which overexpresses netrin-1 in proximal tubular epithelial cells. Fibrosis was associated with increased expression of IL-6 and extensive and chronic activation of STAT3. Administration of IL-6 exacerbated fibrosis in vivo in wild-type, but not in netrin-1 transgenic mice kidney and increased collagen I expression and STAT3 activation in vitro in renal epithelial cells subjected to hypoxia-reoxygenation, which was suppressed by netrin-1. Our data suggest that proximal tubular epithelial cells may play a prominent role in interstitial fibrosis and that netrin-1 could be a useful therapeutic agent for treating kidney fibrosis.

scholarly journals Multiparametric MRI detects longitudinal evolution of folic acid-induced nephropathy in mice

2018 ◽  
Vol 315 (5) ◽  
pp. F1252-F1260 ◽  
Author(s):  
Kai Jiang ◽  
Tristan A. Ponzo ◽  
Hui Tang ◽  
Prasanna K. Mishra ◽  
Slobodan I. Macura ◽  
...  
Keyword(s):  
Folic Acid ◽  
Interstitial Fibrosis ◽  
Magnetization Transfer ◽  
Kidney Injury ◽  
Multiparametric Mri ◽  
Magnetization Transfer Ratio ◽  
Kidney Volume ◽  
Kidney Size ◽  
Functional Changes

The rodent model of folic acid (FA)-induced acute kidney injury (AKI) provides a useful model for studying human AKI, but little is known about longitudinal changes in renal hemodynamics and evolution of renal fibrosis in vivo. In this work, we aimed to longitudinally assess renal structural and functional changes using multiparametric magnetic resonance imaging (MRI). Ten adult mice were injected with FA, after which a multiparametric MRI was used to measure kidney volume, hypoxia index R2*, magnetization transfer ratio (MTR), perfusion, T1, and glomerular filtration rate (GFR) at 2 wk posttreatment. Then five mice were euthanized for histology, and the other five underwent MRI again at 4 wk, followed by histology. Control mice ( n = 5) were injected with vehicle and studied with MRI at 2 wk. Trichrome and hematoxylin-eosin staining were performed to assess FA-induced tissue injuries. Whereas kidney size and oxygenation showed progressive deterioration, a transient impairment in renal perfusion and normalized GFR slightly improved by 4 wk. Kidney fluid content, as reflected by T1, was prominent at 2 wk and tended to regress at 4 wk, consistent with observed tubular dilation. Trichrome staining revealed patchy necrosis and mild interstitial fibrosis at 2 wk, which exacerbated at 4 wk. MTR detected increased fibrosis at 4 wk. In conclusion, multiparametric MRI captured the longitudinal progression in kidney damage evolving within the first month after treatment with folic acid and may provide a useful tool for assessment of therapeutic strategies.

scholarly journals Renoprotective effects of a novel cMet agonistic antibody on kidney fibrosis

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Yong Chul Kim ◽  
Junghun Lee ◽  
Jung Nam An ◽  
Jin Hyuk Kim ◽  
Young-Wook Choi ◽  
...  
Keyword(s):  
Kidney Diseases ◽  
Active Form ◽  
Kidney Injury ◽  
Biologically Active ◽  
Kidney Fibrosis ◽  
Proximal Tubular Epithelial Cells ◽  
Proximal Tubular ◽  
A Cell ◽  
Masson Trichrome Staining ◽  
Hepatocyte Growth

Abstract Hepatocyte growth factor (HGF) and its receptor, cMet, activate biological pathways necessary for repair and regeneration following kidney injury. Because HGF is a highly unstable molecule in its biologically active form, we asked whether a monoclonal antibody (Ab) that displays full agonist activity at the receptor could protect the kidney from fibrosis. We attempted to determine whether the cMet agonistic Ab might reduce fibrosis, the final common pathway for chronic kidney diseases (CKD). A mouse model of kidney fibrosis disease induced by unilateral ureteral obstruction was introduced and subsequently validated with primary cultured human proximal tubular epithelial cells (PTECs). In kidney biopsy specimens from patients with CKD, cMet immunohistochemistry staining showed a remarkable increase compared with patients with normal renal functions. cMet Ab treatment significantly increased the levels of phospho-cMet and abrogated the protein expression of fibrosis markers such as fibronectin, collagen 1, and αSMA as well as Bax2, which is a marker of apoptosis triggered by recombinant TGF-β1 in PTECs. Remarkably, injections of cMet Ab significantly prevented kidney fibrosis in obstructed kidneys as quantified by Masson trichrome staining. Consistent with these data, cMet Ab treatment decreased the expression of fibrosis markers, such as collagen1 and αSMA, whereas the expression of E-cadherin, which is a cell-cell adhesion molecule, was restored. In conclusion, cMet-mediated signaling may play a considerable role in kidney fibrosis. Additionally, the cMet agonistic Ab may be a valuable substitute for HGF because it is more easily available in a biologically active, stable, and purified form.

scholarly journals Targeting the RNA-Binding Protein QKI in Myeloid Cells Ameliorates Macrophage-Induced Renal Interstitial Fibrosis

Epigenomes ◽  
2020 ◽  
Vol 4 (1) ◽  
pp. 2
Author(s):  
Ruben G. de Bruin ◽  
Gillian Vogel ◽  
Jurrien Prins ◽  
Jacques M. J. G. Duijs ◽  
Roel Bijkerk ◽  
...  
Keyword(s):  
Rna Binding ◽  
Interstitial Fibrosis ◽  
Kidney Diseases ◽  
Cell Lineage ◽  
Kidney Injury ◽  
Myeloid Cell ◽  
Mrna Splicing ◽  
Transcriptional Level ◽  
Renal Interstitial Fibrosis ◽  
Splice Regulator

In the pathophysiologic setting of acute and chronic kidney injury, the excessive activation and recruitment of blood-borne monocytes prompts their differentiation into inflammatory macrophages, a process that leads to progressive glomerulosclerosis and interstitial fibrosis. Importantly, this differentiation of monocytes into macrophages requires the meticulous coordination of gene expression at both the transcriptional and post-transcriptional level. The transcriptomes of these cells are ultimately determined by RNA-binding proteins such as QUAKING (QKI), that define their pre-mRNA splicing and mRNA transcript patterns. Using two mouse models, namely (1) quaking viable mice (qkv) and (2) the conditional deletion in the myeloid cell lineage using the lysozyme 2-Cre (QKIFL/FL;LysM-Cre mice), we demonstrate that the abrogation of QKI expression in the myeloid cell lineage reduces macrophage infiltration following kidney injury induced by unilateral urethral obstruction (UUO). The qkv and QKIFL/FL;LysM-Cre mice both showed significant diminished interstitial collagen deposition and fibrosis in the UUO-damaged kidney, as compared to wild-type littermates. We show that macrophages isolated from QKIFL/FL;LysM-Cre mice are associated with defects in pre-mRNA splicing. Our findings demonstrate that reduced expression of the alternative splice regulator QKI in the cells of myeloid lineage attenuates renal interstitial fibrosis, suggesting that inhibition of this splice regulator may be of therapeutic value for certain kidney diseases.

scholarly journals Macrophage Phenotype in Kidney Injury and Repair

2015 ◽  
Vol 1 (2) ◽  
pp. 138-146 ◽  
Author(s):  
Xiao-Ming Meng ◽  
Patrick Ming-Kuen Tang ◽  
Jun Li ◽  
Hui Yao Lan
Keyword(s):  
Renal Injury ◽  
Kidney Diseases ◽  
Kidney Injury ◽  
Renal Diseases ◽  
Macrophage Phenotype ◽  
M1 Macrophages ◽  
Chronic Kidney Diseases ◽  
Chronic Kidney Injury ◽  
Injury And Repair ◽  
And Function

Background: Glomerular and interstitial macrophage infiltration is a feature for both the acute and chronic kidney diseases. Macrophages have been shown to play a diverse role in kidney injury and repair. Thus, macrophages may be a key cell type in acute and chronic kidney injury and repair. Summary and Key Messages: During renal inflammation, circulating monocytes are recruited and then become activated and polarized. By adapting to the local microenvironment, macrophages can differentiate into different phenotypes and function as a double-bladed sword in different stages of kidney disease. In general, M1 macrophages play a pathogenic role in boosting inflammatory renal injury, whereas M2 macrophages exert an anti-inflammatory and wound healing (or profibrotic) role during renal repair. In this review, we highlight the phenotypic polarization of macrophages in renal diseases and dissect their distinct functions in renal injury and repair processes, respectively. Moreover, the current understanding of regulatory mechanisms on the phenotypic switch and macrophage-related therapy are also intensively discussed.

scholarly journals In vitro study on effect of bardoxolone methyl on cisplatin-induced cellular senescence in human proximal tubular cells

2022 ◽  
Author(s):  
Yoshifumi Kurosaki ◽  
Akemi Imoto ◽  
Fumitaka Kawakami ◽  
Motoshi Ouchi ◽  
Asuka Morita ◽  
...  
Keyword(s):  
Cellular Senescence ◽  
Kidney Diseases ◽  
Kidney Injury ◽  
In Vitro Study ◽  
Tunel Staining ◽  
Epithelial Cell Line ◽  
Dependent Manner ◽  
Proximal Tubular ◽  
Induced Apoptosis

AbstractBardoxolone methyl [methyl-2-cyano-3, 12-dioxooleana-1, 9(11)dien-28-oate (CDDO-Me)], an activator of the nuclear factor erythroid-derived 2-related factor2 pathway, is a potential therapeutic candidate for the treatment of kidney diseases. However, its effect against cellular senescence remains unclear. This study aimed to investigate whether CDDO-Me protects cells against cisplatin-induced cellular senescence using an in vitro model. The human renal proximal tubular epithelial cell line HK-2 was treated with cisplatin for 6 h, followed by treatment with or without CDDO-Me (0.1 or 0.2 μmol/L). Senescence markers were analyzed using western blotting and real-time PCR. Apoptosis was evaluated through TUNEL staining. Cisplatin induced changes in the levels of markers specific for proliferation, cell cycle, and senescence in a time- and dose-dependent manner. Furthermore, IL-6 and IL-8 levels in the culture medium increased markedly. These data suggested that cellular senescence-like alterations occurred in HK-2 cells exposed to cisplatin. CDDO-Me treatment reversed the cisplatin-mediated alterations in the levels of cellular senescence markers. The antioxidant enzymes, HO1, NQO1, GPX1, and CAT were upregulated by CDDO-Me treatment. Furthermore, CDDO-Me treatment induced apoptosis in cisplatin-exposed HK-2 cells. Pretreatment with Ac-DEVD-CHO, the caspase inhibitor, suppressed the reversal effect of CDDO-Me against cisplatin-induced cellular senescence-like alterations. This study showed that CDDO-Me attenuated cisplatin-induced premature senescence of HK-2 cells. This beneficial effect may be related to Nrf2 activation. Our findings also showed that CDDO-Me induced apoptosis in cisplatin-treated HK-2 cells, potentially protecting the kidneys from cellular senescence. CDDO-Me appears to be a candidate treatment for acute kidney injury.

Decreased IFT88 expression with primary cilia shortening causes mitochondrial dysfunction in cisplatin-induced tubular injury

2021 ◽  
Author(s):  
Rie Fujii ◽  
Sho Hasegawa ◽  
Hiroshi Maekawa ◽  
Tsuyoshi Inoue ◽  
Kentaro Yoshioka ◽  
...  
Keyword(s):  
Mitochondrial Dysfunction ◽  
Primary Cilia ◽  
Kidney Injury ◽  
Intraflagellar Transport ◽  
Acid Oxidation ◽  
Tubular Damage ◽  
Tubular Injury ◽  
Atp Production ◽  
Tubular Cells ◽  
Proximal Tubular

The relevance of primary cilia shortening in kidney disease and its pathomechanism are largely unknown. Tubular damage in acute kidney injury (AKI) is strongly associated with mitochondrial dysfunction. Thus, we investigated the interaction between primary cilia and mitochondria in cisplatin-induced AKI mouse models. We observed that the expression of intraflagellar transport 88 (IFT88), a ciliary maintenance protein, was decreased in the renal cortex following tubular damage due to cisplatin-induced AKI. This result was consistent with the decreased IFT88 expression in cisplatin-treated RPTEC/TERT1 cells-human primary proximal tubular cells-parallel to the shortening of primary cilia, suggesting a causative link between tubular damage and IFT88-mediated cilia regulation. To address the effect of impaired primary cilia with decreased IFT88 expression on tubular function, RPTEC/TERT1 cells treated with cisplatin and knocked down for IFT88 using siRNA (IFT88-KD) were assessed for phenotypic changes and mitochondrial metabolic function. Both cisplatin and IFT88-KD caused primary cilia shortening, downregulated mitochondrial oxidative phosphorylation capacity, defective fatty acid oxidation (FAO), and decreased ATP production. Furthermore, IFT88 overexpression enhanced mitochondrial respiration, which partially counteracted cisplatin-induced defective FAO. These results are indicative of the contribution of IFT88 to mitochondrial homeostasis. Our findings suggest that tubular mitochondrial dysfunction in cisplatin-induced AKI is mediated, at least in part, by a decrease in IFT88 expression with primary cilia shortening. That is, tubular mitochondrial damage followed by tubular injury in AKI may occur through alteration of IFT88 expression and subsequent ciliary shortening in tubular cells.

Blockade of cysteine-rich protein 61 attenuates renal inflammation and fibrosis after ischemic kidney injury

2014 ◽  
Vol 307 (5) ◽  
pp. F581-F592 ◽  
Author(s):  
Chun-Fu Lai ◽  
Shuei-Liong Lin ◽  
Wen-Chih Chiang ◽  
Yung-Ming Chen ◽  
Vin-Cent Wu ◽  
...  
Keyword(s):  
Transforming Growth Factor ◽  
Interstitial Fibrosis ◽  
Smooth Muscle Actin ◽  
Ischemia Reperfusion ◽  
Kidney Injury ◽  
Monocyte Chemoattractant Protein 1 ◽  
Monocyte Chemoattractant ◽  
Monocyte Chemoattractant Protein ◽  
Cysteine Rich Protein ◽  
Proximal Tubular

Emerging data have suggested that acute kidney injury (AKI) is often incompletely repaired and can lead to chronic kidney disease (CKD), which is characterized by tubulointerstitial inflammation and fibrosis. However, the underlying mechanisms linking AKI to CKD remain obscure. The present study aimed to investigate the role of cysteine-rich protein 61 (Cyr61) after unilateral kidney ischemia-reperfusion injury (IRI) in mice. After IRI, increased expression of Cyr61 was detected, predominately in the proximal tubular epithelium. This was confirmed by in vitro experiments, which showed that hypoxia stimulated Cyr61 expression in cultured proximal tubular epithelial cells. The proinflammatory property of Cyr61 was indicated by its ability to upregulate monocyte chemoattractant protein-1 and IL-6. Additionally, we found elevated urinary Cyr61 excretion in patients with AKI. Notably, treatment of mice with an anti-Cyr61 antibody attenuated the upregulation of kidney monocyte chemoattractant protein-1, IL-6, IL-1β, and macrophage inflammatory protein-2 and reduced the infiltration of F4/80-positive macrophages on days 7 and 14 after IRI. In addition, blockade of Cyr61 reduced the mRNA expression of collagen, transforming growth factor-β, and plasminogen activator inhibitor-I as well as the degree of collagen fibril accumulation, as evaluated by picrosirius red staining, and levels of α-smooth muscle actin proteins by day 14. Concurrently, in the treated group, peritubular microvascular density was more preserved on day 14. We conclude that Cyr61 blockade inhibits the triad of inflammation, interstitial fibrosis, and capillary rarefaction after severe ischemic AKI. The results of this study expand the knowledge of the mechanisms underlying the AKI-to-CKD transition and suggest that Cyr61 is a potential therapeutic target.

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