scholarly journals Inhibition of PTEN Activity Aggravates Post Renal Fibrosis in Mice with Ischemia Reperfusion-Induced Acute Kidney Injury

2017 ◽  
Vol 43 (5) ◽  
pp. 1841-1854 ◽  
Author(s):  
Jun Zhou ◽  
Jiying  Zhong ◽  
Sen  Lin ◽  
Zhenxing Huang ◽  
Hongtao Chen ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Acute Kidney Injury ◽  
Kidney Disease ◽  
Renal Fibrosis ◽  
Smooth Muscle Actin ◽  
Ischemia Reperfusion ◽  
Specific Inhibitor ◽  
Kidney Injury ◽  
Control Group ◽  
Kidney Fibrosis

Background: Renal fibrosis is a common pathophysiological feature of chronic kidney disease. Acute kidney injury (AKI) is defined as an independent causal factor of chronic kidney disease, with a pathological representation of post renal fibrosis. However, the etiopathogenesis underlying post renal fibrosis induced by AKI is not completely understood. Methods: BALB/c mice were treated with bpv or vehicle controls and were, respectively, the ischemia reperfusion (IR) model group and control group. All of the animals had blood taken from the orbital venous plexus at 24 hours after IR. Six mice in each group were randomly chosen and euthanized 7 days after IR treatment, and the remaining six mice in each group were euthanized 14 days after IR treatment. We examined the effect on post kidney fibrosis of inhibiting PTEN activity in mice in an IR induced AKI experimental model. Results: Compared with vehicle mice, bpv-(PTEN specific inhibitor) treated mice accumulated more bone marrow-derived fibroblasts and myofibroblasts in the kidneys. Inhibition of PTEN activity increased the expression of α-smooth muscle actin and extracellular matrix proteins and post kidney fibrosis. Furthermore, inhibition of PTEN activity resulted in more inflammatory cytokines in the kidneys of mice subjected to IR-induced renal fibrosis. Moreover, inhibition of PTEN activity up-regulated PI3K protein expression and Akt phosphorylation. Conclusions: Our study demonstrated that PTEN played an important role in post renal fibrosis in mice with ischemia reperfusion-induced AKI. These results indicated that the PTEN/PI3K/Akt signaling pathway may serve as a novel therapeutic target for AKI-induced chronic kidney disease.

The Long Noncoding RNA-H19 Mediates the Progression of Fibrosis from Acute Kidney Injury to Chronic Kidney Disease by Regulating the miR-196a/Wnt/β-Catenin Signaling

Nephron ◽  
2021 ◽  
pp. 1-11
Author(s):  
Xiangnan Dong ◽  
Rui Cao ◽  
Qiang Li ◽  
Lianghong Yin
Keyword(s):  
Chronic Kidney Disease ◽  
Acute Kidney Injury ◽  
Kidney Disease ◽  
Noncoding Rna ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Kidney Injury ◽  
Collagen I ◽  
Luciferase Reporter ◽  
Kidney Fibrosis

<b><i>Introduction:</i></b> Long noncoding RNAs (lncRNAs) have been reported to be involved in the occurrence and development of various diseases. This study was to investigate the role of lncRNA-H19 in the transition from acute kidney injury (AKI) to chronic kidney disease (CKD) and its underlying mechanism. <b><i>Methods:</i></b> Bilateral renal pedicle ischemia-reperfusion injury (IRI) was used to establish the IRI-AKI model in C57BL/6 mice. The expression levels of lncRNA-H19, miR-196a-5p, α-SMA, collagen I, Wnt1, and β-catenin in mouse kidney tissues and fibroblasts were determined by quantitative real-time PCR and Western blotting. The degree of renal fibrosis was evaluated by hematoxylin and eosin staining. The interaction between lncRNA-H19 and miR-196a-5p was verified by bioinformatics analysis and luciferase reporter assay. Immunohistochemistry and immunofluorescence were used to evaluate the expression of α-SMA and collagen I in kidney tissues and fibroblasts of mice. <b><i>Results:</i></b> lncRNA-H19 is upregulated, and miR-196a-5p is downregulated in kidney tissues of IRI mice. Moreover, miR-196a-5p is a direct target of lncRNA-H19. lncRNA-H19 overexpression promotes kidney fibrosis and activates fibroblasts during AKI-CKD development, while miR-196a-5p overexpression reversed these effects in vitro. Furthermore, lncRNA-H19 overexpression significantly upregulates Wnt1 and β-catenin expression in kidney tissues and fibroblasts of IRI mice, while miR-196a-5p overexpression downregulates Wnt1 and β-catenin expression in kidney tissues and fibroblasts of IRI mice. <b><i>Conclusion:</i></b> lncRNA-H19 induces kidney fibrosis during AKI-CKD by regulating the miR-196a-5p/Wnt/β-catenin signaling pathway.

scholarly journals cMet agonistic antibody prevents acute kidney injury to chronic kidney disease transition by suppressing Smurf1 and activating Smad7

2021 ◽  
Author(s):  
Lilin Li ◽  
Jeonghwan Lee ◽  
Ara Cho ◽  
Jin Hyuk Kim ◽  
Wonmin Ju ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Acute Kidney Injury ◽  
Kidney Disease ◽  
Ischemia Reperfusion ◽  
Kidney Injury ◽  
Smad Pathway ◽  
Agonistic Antibody ◽  
Kidney Fibrosis ◽  
Tgf Β1

We aimed to investigate the role of cMet agonistic antibody (cMet Ab) in preventing kidney fibrosis during acute kidney injury (AKI) to chronic kidney disease (CKD) transition. Additionally, we explored the effect of cMet Ab on TGF-β1/Smad pathway during the pathogenesis of kidney fibrosis. A unilateral ischemia-reperfusion injury (UIRI) mouse model was established to induce AKI-to-CKD transition. Furthermore, we incubated human proximal tubular epithelial cells under hypoxic conditions as in vitro model of kidney fibrosis. We analyzed the soluble plasma cMet level in patients with AKI requiring dialysis. Patients who did not recover kidney function and progressed to CKD presented a higher increase in the cMet level. The kidneys of mice treated with cMet Ab showed fewer contractions and weighed more than the controls. The mice in the cMet Ab-treated group showed reduced fibrosis and significantly decreased expression of fibronectin and α-smooth muscle actin. cMet Ab treatment decreased inflammatory marker (MCP-1, TNF-α, and IL-1β) expression, reduced Smurf1 and Smad2/3 level, and increased Smad7 expressions. cMet Ab treatment increased cMet expression and reduced the hypoxia-induced increase in collagen-1 and ICAM-1 expression, thereby reducing apoptosis in the in vitro cell model. After cMet Ab treatment, hypoxia-induced expression of Smurf1, Smad2/3, and TGF-β1 was reduced, and suppressed Smad7 was activated. Down-regulation of Smurf1 resulted in suppression of hypoxia-induced fibronectin expression, whereas treatment with cMet Ab showed synergistic effects. cMet Ab can successfully prevent fibrosis response in UIRI models of kidney fibrosis by decreasing inflammatory response and inhibiting the TGF-β1/Smad pathway.

scholarly journals PGC1α in the kidney

2018 ◽  
Vol 314 (1) ◽  
pp. F1-F8 ◽  
Author(s):  
Matthew R. Lynch ◽  
Mei T. Tran ◽  
Samir M. Parikh
Keyword(s):  
Chronic Kidney Disease ◽  
Acute Kidney Injury ◽  
Kidney Disease ◽  
Renal Fibrosis ◽  
Diabetic Kidney Disease ◽  
Kidney Injury ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
The Relationship ◽  
Prime Target

Acute kidney injury (AKI) arising from diverse etiologies is characterized by mitochondrial dysfunction. The peroxisome proliferator-activated receptor γ coactivator-1alpha (PGC1α), a master regulator of mitochondrial biogenesis, has been shown to be protective in AKI. Interestingly, reduction of PGC1α has also been implicated in the development of diabetic kidney disease and renal fibrosis. The beneficial renal effects of PGC1α make it a prime target for therapeutics aimed at ameliorating AKI, forms of chronic kidney disease (CKD), and their intersection. This review summarizes the current literature on the relationship between renal health and PGC1α and proposes areas of future interest.

scholarly journals Orai1: A New Therapeutic Target for the Acute Kidney Injury-to-Chronic Kidney Disease Transition

Nephron ◽  
2021 ◽  
pp. 1-4
Author(s):  
David P. Basile ◽  
Jason A. Collett
Keyword(s):  
Chronic Kidney Disease ◽  
Acute Kidney Injury ◽  
Kidney Disease ◽  
Peripheral Blood ◽  
Th17 Cells ◽  
Ischemia Reperfusion ◽  
Kidney Injury ◽  
Acute Injury ◽  
Chronic Kidney Injury ◽  
Sustained Increase

This review focuses on the potential mediation in the acute kidney injury (AKI)-to-chronic kidney disease (CKD) transition by lymphocytes. We highlight evidence that lymphocytes, particularly Th17 cells, modulate the severity of both acute injury and chronic kidney disease. Th17 cells are strongly influenced by the activity of the store-operated Ca<sup>2+</sup>channel Orai1, which is upregulated on lymphocytes in animal models of AKI. Inhibition of this channel attenuates both acute and chronic kidney injury in rodent models. In addition, Oria1+ cells are increased in peripheral blood of patients with AKI. Similarly, peripheral blood cells manifest an early and sustained increase in Orai1 expression in a rat model of ischemia/reperfusion, suggesting that blood cell Orai1 may represent a marker informing potential Th17 activity in the setting of AKI or the AKI-to-CKD transition.

scholarly journals Lymphocytes: Versatile Participants in Acute Kidney Injury and Progression to Chronic Kidney Disease

2021 ◽  
Vol 12 ◽  
Author(s):  
Chujin Cao ◽  
Ying Yao ◽  
Rui Zeng
Keyword(s):  
Chronic Kidney Disease ◽  
Acute Kidney Injury ◽  
Kidney Disease ◽  
Renal Injury ◽  
Renal Fibrosis ◽  
Kidney Injury ◽  
Renal Parenchyma ◽  
Health Concern ◽  
High Morbidity ◽  
Parenchyma Cells

Background: Acute kidney injury (AKI) remains a major global public health concern due to its high morbidity and mortality. The progression from AKI to chronic kidney disease (CKD) makes it a scientific problem to be solved. However, it is with lack of effective treatments.Summary: Both innate and adaptive immune systems participate in the inflammatory process during AKI, and excessive or dysregulated immune responses play a pathogenic role in renal fibrosis, which is an important hallmark of CKD. Studies on the pathogenesis of AKI and CKD have clarified that renal injury induces the production of various chemokines by renal parenchyma cells or resident immune cells, which recruits multiple-subtype lymphocytes in circulation. Some infiltrated lymphocytes exacerbate injury by proinflammatory cytokine production, cytotoxicity, and interaction with renal resident cells, which constructs the inflammatory environment and induces further injury, even death of renal parenchyma cells. Others promote tissue repair by producing protective cytokines. In this review, we outline the diversity of these lymphocytes and their mechanisms to regulate the whole pathogenic stages of AKI and CKD; discuss the chronological responses and the plasticity of lymphocytes related to AKI and CKD progression; and introduce the potential therapies targeting lymphocytes of AKI and CKD, including the interventions of chemokines, cytokines, and lymphocyte frequency regulation in vivo, adaptive transfer of ex-expanded lymphocytes, and the treatments of gut microbiota or metabolite regulations based on gut-kidney axis.Key Message: In the process of AKI and CKD, T helper (Th) cells, innate, and innate-like lymphocytes exert mainly pathogenic roles, while double-negative T (DNT) cells and regulatory T cells (Tregs) are confirmed to be protective. Understanding the mechanisms by which lymphocytes mediate renal injury and renal fibrosis is necessary to promote the development of specific therapeutic strategies to protect from AKI and prevent the progression of CKD.

scholarly journals Huaier Extract Attenuates Acute Kidney Injury to Chronic Kidney Disease Transition by Inhibiting Endoplasmic Reticulum Stress and Apoptosis via miR-1271 Upregulation

2020 ◽  
Vol 2020 ◽  
pp. 1-8
Author(s):  
Jing-Ying Zhao ◽  
Yu-Bin Wu
Keyword(s):  
Chronic Kidney Disease ◽  
Acute Kidney Injury ◽  
Endoplasmic Reticulum ◽  
Kidney Disease ◽  
Endoplasmic Reticulum Stress ◽  
Molecular Mechanisms ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Kidney Injury

Endoplasmic reticulum stress (ERS) is strongly associated with acute kidney injury (AKI) to chronic kidney disease (CKD) transition. Huaier extract (HE) protects against kidney injury; albeit, the underlying mechanism is unknown. We hypothesized that HE reduces kidney injury by inhibiting ERS. In this study, using an AKI-CKD mouse model of ischemia-reperfusion injury (IRI), we evaluated the effect of HE on AKI-CKD transition. We also explored the underlying molecular mechanisms in this animal model and in the HK-2 human kidney cell line. The results showed that HE treatment improved the renal function, demonstrated by a significant decrease in serum creatinine levels after IRI. HE appreciably reduced the degree of kidney injury and fibrosis and restored the expression of the microRNA miR-1271 after IRI. Furthermore, HE reduced the expression of ERS markers glucose-regulated protein 78 (GRP78) and C/EBP homologous protein (CHOP) and inhibited apoptosis in the IRI group. This in vivo effect was supported by in vitro results in which HE inhibited apoptosis and decreased the expression of CHOP and GRP78 induced by ERS. We demonstrated that CHOP is a target of miR-1271. In conclusion, HE reduces kidney injury, probably by inhibiting apoptosis and decreasing the expression of GRP78 and CHOP via miR-1271 upregulation.

scholarly journals Metabolomic and biochemical characterization of a new model of the transition of acute kidney injury to chronic kidney disease induced by folic acid

PeerJ ◽  
2019 ◽  
Vol 7 ◽  
pp. e7113
Author(s):  
Marlene Marisol Perales-Quintana ◽  
Alma L. Saucedo ◽  
Juan Ricardo Lucio-Gutiérrez ◽  
Noemí Waksman ◽  
Gabriela Alarcon-Galvan ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Acute Kidney Injury ◽  
Folic Acid ◽  
Kidney Disease ◽  
Biochemical Parameters ◽  
Kidney Injury ◽  
Renal Diseases ◽  
Control Group ◽  
Organic Osmolytes ◽  
Histological Classification

Background Renal diseases represent a major public health problem. The demonstration that maladaptive repair of acute kidney injury (AKI) can lead to the development of chronic kidney disease (CKD) and end-stage renal disease has generated interest in studying the pathophysiological pathways involved. Animal models of AKI–CKD transition represent important tools to study this pathology. We hypothesized that the administration of multiple doses of folic acid (FA) would lead to a progressive loss of renal function that could be characterized through biochemical parameters, histological classification and nuclear magnetic resonance (NMR) profiling. Methods Wistar rats were divided into groups: the control group received a daily intraperitoneal (I.P.) injection of double-distilled water, the experimental group received a daily I.P. injection of FA (250 mg kg body weight−1). Disease was classified according to blood urea nitrogen level: mild (40–80 mg dL−1), moderate (100–200 mg dL−1) and severe (>200 mg dL−1). We analyzed through biochemical parameters, histological classification and NMR profiling. Results Biochemical markers, pro-inflammatory cytokines and kidney injury biomarkers differed significantly (P < 0.05) between control and experimental groups. Histology revealed that as damage progressed, the degree of tubular injury increased, and the inflammatory infiltrate was more evident. NMR metabolomics and chemometrics revealed differences in urinary metabolites associated with CKD progression. The main physiological pathways affected were those involved in energy production and amino-acid metabolism, together with organic osmolytes. These data suggest that multiple administrations of FA induce a reproducible model of the induction of CKD. This model could help to evaluate new strategies for nephroprotection that could be applied in the clinic.

scholarly journals New mouse model of chronic kidney disease transitioned from ischemic acute kidney injury

2019 ◽  
Vol 317 (2) ◽  
pp. F286-F295 ◽  
Author(s):  
Jin Wei ◽  
Jie Zhang ◽  
Lei Wang ◽  
Shan Jiang ◽  
Liying Fu ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Acute Kidney Injury ◽  
Glomerular Filtration Rate ◽  
Kidney Disease ◽  
Reperfusion Injury ◽  
Glomerular Filtration ◽  
Filtration Rate ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Kidney Injury

Acute kidney injury (AKI) significantly increases the risk of development of chronic kidney disease (CKD), which is closely associated with the severity of AKI. However, the underlying mechanisms for the AKI to CKD transition remain unclear. Several animal models with AKI to CKD transition have been generated and widely used in research; however, none of them exhibit the typical changes in glomerular filtration rate or plasma creatinine, the hallmarks of CKD. In the present study, we developed a novel model with a typical phenotype of AKI to CKD transition in C57BL/6 mice. In this model, life-threatening ischemia-reperfusion injury was performed in one kidney, whereas the contralateral kidney was kept intact to maintain animal survival; then, after 2 wk of recovery, when the renal function of the injured kidney restored above the survival threshold, the contralateral intact kidney was removed. Animals of this two-stage unilateral ischemia-reperfusion injury model with pedicle clamping of 21 and 24 min exhibited an incomplete recovery from AKI and subsequent progression of CKD with characteristics of a progressive decline in glomerular filtration rate, increase in plasma creatinine, worsening of proteinuria, and deleterious histopathological changes, including interstitial fibrosis and glomerulosclerosis. In conclusion, a new model of the AKI to CKD transition was generated in C57BL/6 mice.

scholarly journals P0547THE DELETION OF AKT1 ATTENUATES RENAL FIBROSIS AND TUBULAR EPITHELIAL-MESENCHYMAL TRANSITION DURING ACUTE KIDNEY INJURY TO CHRONIC KIDNEY DISEASE PROGRESSION

2020 ◽  
Vol 35 (Supplement_3) ◽  
Author(s):  
Byung Min Ye ◽  
Il Young Kim ◽  
Min Jeong Kim ◽  
Soo Bong Lee ◽  
Dong Won Lee ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Acute Kidney Injury ◽  
Kidney Disease ◽  
Renal Fibrosis ◽  
Epithelial Mesenchymal Transition ◽  
Kidney Injury ◽  
Wild Type ◽  
Ckd Progression ◽  
Mesenchymal Transition ◽  
Tgf Β1

Abstract Background and Aims Acute kidney injury (AKI) is an underestimated, yet important risk factor for the development of chronic kidney disease (CKD), which is characterized by the tubulointerstitial fibrosis and tubular epithelial-mesenchymal transition (EMT). Akt has been reported to be involved in renal fibrosis and EMT. Thus, we investigated the role of Akt1, one of the three Akt isoforms, in the murine model of AKI to CKD progression. Method We subjected the wild type and Akt1−/− mice to unilateral ischemia-reperfusion injury (UIRI). UIRI was induced by clamping the left renal artery for 30 min followed by reperfusion. After 6 weeks of UIRI, the renal fibrosis and EMT were assessed by histology, immunohistochemistry, and western blot. Results After 6 weeks after UIRI, we found that Akt1, not Akt2 or Akt3, was activated in UIRI-kidney. The tubulointerstitial fibrosis was significantly alleviated in Akt1−/− mice compared with the wild type (WT) mice. Besides, the deletion of Akt1 decreased the expression of the vimentin and α-SMA and increased the expression of E-cadherin, indicating the suppression of tubular EMT. However, there was no difference in the activity of TGF-β1/Smad signalling, which is the potent inducer of renal fibrosis and EMT, between WT mice and Akt1−/− mice. The deletion of Akt1 also increased the GSK-3β activity and decreased the expression of β-catenin, Snail, and twist1. Conclusion Our findings demonstrate that the deletion of Akt1 attenuates the renal fibrosis and tubular EMT independently of TGF-β1/Smad signalling during the AKI to CKD progression. Akt1 may be the therapeutic target against the AKI to CKD progression.

scholarly journals Recruitment and subsequent proliferation of bone marrow-derived cells in the postischemic kidney are important to the progression of fibrosis

2014 ◽  
Vol 306 (12) ◽  
pp. F1451-F1461 ◽  
Author(s):  
Hee-Seong Jang ◽  
Jee In Kim ◽  
Sang Jun Han ◽  
Kwon Moo Park
Keyword(s):  
Chronic Kidney Disease ◽  
Bone Marrow ◽  
Kidney Disease ◽  
Fluorescent Protein ◽  
Smooth Muscle Actin ◽  
Ischemia Reperfusion ◽  
Interstitial Cells ◽  
Kidney Fibrosis ◽  
Bone Marrow Derived Cells

Acute kidney injury (AKI) is an independent risk factor of the development of chronic kidney disease. Kidney fibrosis is a typical feature of chronic kidney disease and is characterized as an expansion of the interstitium due to increases in extracellular matrix molecules and interstitial cells caused by accumulations of extrarenal cells and by the proliferation or differentiation of intrarenal cells. However, the role of bone marrow-derived cells (BMDCs) in AKI-induced kidney fibrosis remains to be defined. Here, we investigated the role of BMDCs in kidney fibrosis after ischemia-reperfusion injury (IRI)-induced AKI in green fluorescent protein (GFP)-expressing bone marrow chimeric mice. IRI resulted in severe fibrotic changes in kidney tissues and dramatically increased interstitial cell numbers. Furthermore, GFP-expressing BMDCs accounted for >80% of interstitial cells in fibrotic kidneys. Interstitial GFP-expressing cells expressed α-smooth muscle actin (a myofibroblast marker), fibroblast-specific protein-1 (a fibroblast marker), collagen type III, and F4/80 (a macrophage marker). Over 20% of interstitial cells were bromodeoxyuridine-incorporating (proliferating) cells, and of these, 80% cells were GFP-expressing BMDCs. Daily treatment of IRI mice with apocynin (a NADPH oxidase inhibitor that functions as an antioxidant) from the day after surgery until euthanization slightly inhibited these changes with a small reduction of fibrosis. Taken together, our findings show that BMDCs make a major contribution to IRI-induced fibrosis due to their infiltration, subsequent differentiation, and proliferation in injured kidneys, suggesting that BMDCs be considered an important target for the treatment of kidney fibrosis.

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