Delayed Contralateral Nephrectomy Halted Post-Ischemic Renal Fibrosis Progression and Inhibited the Ischemia-Induced Fibromir Upregulation in Mice

(1) Background: Ischemia reperfusion (IR) is the leading cause of acute kidney injury (AKI) and results in predisposition to chronic kidney disease. We demonstrated that delayed contralateral nephrectomy (Nx) greatly improved the function of the IR-injured kidney and decelerated fibrosis progression. Our aim was to identify microRNAs (miRNA/miR) involved in this process. (2) Methods: NMRI mice were subjected to 30 min of renal IR and one week later to Nx/sham surgery. The experiments were conducted for 7–28 days after IR. On day 8, multiplex renal miRNA profiling was performed. Expression of nine miRNAs was determined with qPCR at all time points. Based on the target prediction, plexin-A2 and Cd2AP were measured by Western blot. (3) Results: On day 8 after IR, the expression of 20/1195 miRNAs doubled, and 9/13 selected miRNAs were upregulated at all time points. Nx reduced the expression of several ischemia-induced pro-fibrotic miRNAs (fibromirs), such as miR-142a-duplex, miR-146a-5p, miR-199a-duplex, miR-214-3p and miR-223-3p, in the injured kidneys at various time points. Plexin-A2 was upregulated by IR on day 10, while Cd2AP was unchanged. (4) Conclusion: Nx delayed fibrosis progression and decreased the expression of ischemia-induced fibromirs. The protein expression of plexin-A2 and Cd2AP is mainly regulated by factors other than miRNAs.

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

Cellular Physiology and Biochemistry ◽

10.1159/000484070 ◽

2017 ◽

Vol 43 (5) ◽

pp. 1841-1854 ◽

Cited By ~ 14

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.

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PGC1α in the kidney

AJP Renal Physiology ◽

10.1152/ajprenal.00263.2017 ◽

2018 ◽

Vol 314 (1) ◽

pp. F1-F8 ◽

Cited By ~ 26

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.

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Complement inhibition attenuates acute kidney injury after ischemia-reperfusion and limits progression to renal fibrosis in mice

PLoS ONE ◽

10.1371/journal.pone.0183701 ◽

2017 ◽

Vol 12 (8) ◽

pp. e0183701 ◽

Cited By ~ 22

Author(s):

Juan S. Danobeitia ◽

Martynas Ziemelis ◽

Xiaobo Ma ◽

Laura J. Zitur ◽

Tiffany Zens ◽

...

Keyword(s):

Acute Kidney Injury ◽

Renal Fibrosis ◽

Ischemia Reperfusion ◽

Kidney Injury ◽

Complement Inhibition

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

Nephron ◽

10.1159/000518177 ◽

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.

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

Frontiers in Physiology ◽

10.3389/fphys.2021.729084 ◽

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.

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PINK1 Kinase Enhances the Repair Effects of Bone Marrow Mesenchymal Stem Cells on Renal Ischemia/Reperfusion-Induced Acute Kidney Injury in Mice

10.21203/rs.3.rs-1242192/v1 ◽

2022 ◽

Author(s):

Chenyu Lin ◽

Wen Chen ◽

Yong Han ◽

Yujie Sun ◽

Xiaoqiong Zhao ◽

...

Keyword(s):

Stem Cells ◽

Acute Kidney Injury ◽

Mesenchymal Stem Cells ◽

Stress Response ◽

Immune Cells ◽

Peripheral Blood ◽

Ischemia Reperfusion ◽

Kidney Injury ◽

Short Period ◽

Injured Kidney

Abstract Background: Acute kidney injury (AKI) is a common severe acute syndrome caused by multiple causes, which is characterized by a rapid decline of renal function in a short period. Bone mesenchymal stem cells (BMSCs) are effective in the treatment of AKI. However, it remains unclear about the mechanism of their beneficial effects. PENT-induced kinase 1 (PINK1) may play an important role in the kidney tissue repair. In this study, an endeavor would be made to explore the enhancing effect of PINK1 overexpression on the repair of AKI through BMSCs. Methods: In this study, the ischemia/reperfusion-induced acute kidney injury (IRI-AKI) in mice and the hypoxia-reoxygenation model of cells were established, and the indexes were detected by pathology and immunology experimental.Results: After ischemia/reperfusion, compared with the BMSCs group, the OE PINK1 group had a decreased expression of BUN, the mitigated renal fibrosis , the reduced tissue damage degree. Overexpressed PINK1 could decrease the inflammatory reaction of injured kidney tissues in IRI-AKI mice, the decreased expression of IL-10 in peripheral blood serum; and regulate the distribution of immune cells in the kidney during IRI, the decreased infiltration of lymphocytes, the increased infiltration of macrophages; and reduce the stress response of BMSCs under hypoxia and inflammation; and enhance the stress response of BMSCs to renal tubular epithelial cells(RTECs) under hypoxia and inflammation, the decreased apoptosis rate of RTECs, the decreased release of TNF-α in the cell supernatant, and the decreased proliferation of PBMCs in peripheral blood after hypoxia and reoxygenation; and regulate the autophagy of BMSCs in kidney tissues with IRI-AKI to better repair the injured kidney tissues, the increased expression of LC3-B related to autophagy and the decreased expression of mTOR.Conclusions: In this study, PINK1 overexpression enhances the repair effect of BMSCs on IRI-AKI, and the distribution of injured renal immune cells during IRI regulation by BMSCs. Besides, PINK1 enhances BMSCs and their resistance to the stress response of RTECs under hypoxia and inflammation. In addition, it regulates mitophagy during IRI-AKI. The findings of this study provide a new direction and target for the repair of IRI-AKI through BMSCs.

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

BioMed Research International ◽

10.1155/2020/9029868 ◽

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.

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IL-20 in Acute Kidney Injury: Role in Pathogenesis and Potential as a Therapeutic Target

International Journal of Molecular Sciences ◽

10.3390/ijms21031009 ◽

2020 ◽

Vol 21 (3) ◽

pp. 1009

Author(s):

Tian-Yu Lin ◽

Yu-Hsiang Hsu

Keyword(s):

Chronic Kidney Disease ◽

Acute Kidney Injury ◽

Risk Factor ◽

Renal Fibrosis ◽

Inflammatory Mediator ◽

Kidney Diseases ◽

Kidney Injury ◽

Renal Diseases ◽

Pro Inflammatory Cytokines

Acute kidney injury (AKI) causes over 1 million deaths worldwide every year. AKI is now recognized as a major risk factor in the development and progression of chronic kidney disease (CKD). Diabetes is the main cause of CKD as well. Renal fibrosis and inflammation are hallmarks in kidney diseases. Various cytokines contribute to the progression of renal diseases; thus, many drugs that specifically block cytokine function are designed for disease amelioration. Numerous studies showed IL-20 functions as a pro-inflammatory mediator to regulate cytokine expression in several inflammation-mediated diseases. In this review, we will outline the effects of pro-inflammatory cytokines in the pathogenesis of AKI and CKD. We also discuss the role of IL-20 in kidney diseases and provide a potential therapeutic approach of IL-20 blockade for treating renal diseases.

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

AJP Renal Physiology ◽

10.1152/ajprenal.00021.2019 ◽

2019 ◽

Vol 317 (2) ◽

pp. F286-F295 ◽

Cited By ~ 3

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.

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Abstract 301: Testosterone propionate in Ischemia-reperfusion (I/R) induced Acute Kidney Injury (AKI)

Hypertension ◽

10.1161/hyp.64.suppl_1.301 ◽

2014 ◽

Vol 64 (suppl_1) ◽

Author(s):

Chetan N Patil ◽

Rodrigo O Maranon ◽

Carolina Dalmasso ◽

Huimin Zhang ◽

Luis A Juncos ◽

...

Keyword(s):

Acute Kidney Injury ◽

Low Dose ◽

Testosterone Propionate ◽

Therapeutic Potential ◽

Ischemia Reperfusion ◽

Kidney Injury ◽

Causative Factor ◽

Sd Rats ◽

Sham Surgery ◽

Renal Vessels

Acute kidney injury (AKI) is a leading cause of morbidity and mortality, and men are more prone to AKI than women implicating androgens as a causative factor whereas estrogens have been thought to be protective. These effects are independent of both androgen and estrogen receptors. We showed recently that infusion of testosterone 3 hrs post reperfusion protected rats from renal injury following ischemia/reperfusion (I/R). In the present study, we tested the hypothesis that testosterone works as a renal vasodilator perhaps by increasing nitric oxide. Male SD rats (8-14 wks; n=3-5/grp) were subjected to sham surgery or I/R induced AKI with bilateral clamping of renal vessels for 30 min. Three hrs after reperfusion, rats were given testosterone propionate (20 μg/kg iv over 10 min) or vehicle (0.75%EtOH). Rats were placed in metabolism cages for 24hrs for nitrate/nitrite excretion (UNOxV), and euthanized and blood taken for creatinine (PCr). I/R increased PCr and decreased UNOxV, compared to shams (0.58±0.05 vs. 3.99±0.36 mg/dL, p<0.0001; UNOxV: 8.54±1.7 vs 1.7±0.78 μmol/day/kg BW, p<0.001). Testosterone attenuated the increase in PCr (2.03±0.23 mg/dL, p< 0.01) but had no effect on UNOxV (3.79±0.91 μmol/day/kg). Pretreatment of rats with L-NAME (1mg/kg/day; dose that did not increase BP) for 48 hours prior to I/R abolished the improvement in PCr with testosterone (PCr: 3.73±0.82 mg/dL, p<0.05 vs no LNAME). Infusion of renal vasodilator PGE2 (30μg/kg iv over 10 min 3 hrs after reperfusion) attenuated PCr compared to I/R alone (2.95±0.21mg/dL, p<0.01) but was independent of increased NO (2.61±0.63 μmol/day/kg, p=NS vs I/R alone), and was not as effective in reducing PCr as testosterone (p<0.05). These data show that low dose testosterone infusion 3 hrs post reperfusion improves renal function in AKI perhaps by causing renal vasodilation. When NO synthesis is blocked, testosterone is incapable of improving PCr after I/R. Furthermore, although the known renal vasodilator PGE2 also improves PCr in I/R, although not as effectively as testosterone. These data continue to support the notion that testosterone infusion has therapeutic potential for the treatment of I/R induced AKI in humans. Supported by NIH R01HL66072, P01HL05971 and AHA 14POST18640015.

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