Therapeutic potential of regulatory macrophages generated from peritoneal dialysate in adriamycin nephropathy

Cell therapy using macrophages requires large amounts of cells, which are difficult to collect from patients. Patients undergoing peritoneal dialysis (PD) discard huge numbers of peritoneal macrophages in dialysate daily. Macrophages can be modulated to become regulatory macrophages, which have shown great promise as a therapeutic strategy in experimental kidney disease and human kidney transplantation. This study aimed to examine the potential of using peritoneal macrophages (PMs) from peritoneal dialysate to treat kidney disease. Monocytes/macrophages accounted for >40% of total peritoneal leukocytes in both patients and mice undergoing PD. PMs from patients and mice undergoing PD were more mature than peripheral monocytes/macrophages, as shown by low expression of C-C motif chemokine receptor 2 (CCR2) and morphological changes during in vitro culture. PMs from patients and mice undergoing PD displayed normal macrophage function and could be modulated into a regulatory (M2) phenotype. In vivo, adoptive transfer of peritoneal M2 macrophages derived from PD mice effectively protected against kidney injury in mice with adriamycin nephropathy (AN). Importantly, the transfused peritoneal M2 macrophages maintained their M2 phenotype in kidney of AN mice. In conclusion, PMs derived from patients and mice undergoing PD exhibited conventional macrophage features. Peritoneal M2 macrophages derived from PD mice are able to reduce kidney injury in AN, suggesting that peritoneal macrophages from patients undergoing PD may have the potential for clinical therapeutic application.

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Stem cell-based treatment of kidney diseases

Experimental Biology and Medicine ◽

10.1177/1535370220915901 ◽

2020 ◽

Vol 245 (10) ◽

pp. 902-910

Author(s):

Binbin Pan ◽

Guoping Fan

Keyword(s):

Chronic Kidney Disease ◽

Stem Cells ◽

Acute Kidney Injury ◽

Stem Cell ◽

Kidney Disease ◽

Cell Therapy ◽

Kidney Diseases ◽

Kidney Injury ◽

Great Promise ◽

Kidney Organoids

Kidney dysfunction, including chronic kidney disease and acute kidney injury, is a globally prevalent health problem. However, treatment regimens are still lacking, especially for conditions involving kidney fibrosis. Stem cells hold great promise in the treatment of chronic kidney disease and acute kidney injury, but success has been hampered by insufficient incorporation of the stem cells in the injured kidney. Thus, new approaches for the restoration of kidney function after acute or chronic injury have been explored. Recently, kidney organoids have emerged as a useful tool in the treatment of kidney diseases. In this review, we discuss the mechanisms and approaches of cell therapy in acute kidney injury and chronic kidney disease, including diabetic kidney disease and lupus nephritis. We also summarize the potential applications of kidney organoids in the treatment of kidney diseases. Impact statement Stem cells hold great promise in regenerative medicine. Pluripotent stem cells have been differentiated into kidney organoids to understand human kidney development and to dissect renal disease mechanisms. Meanwhile, recent studies have explored the treatment of kidney diseases using a variety of cells, including mesenchymal stem cells and renal derivatives. This mini-review discusses the diverse mechanisms underlying current renal disease treatment via stem cell therapy. We postulate that clinical applications of stem cell therapy for kidney diseases can be readily achieved in the near future.

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ASK1: a new therapeutic target for kidney disease

AJP Renal Physiology ◽

10.1152/ajprenal.00208.2016 ◽

2016 ◽

Vol 311 (2) ◽

pp. F373-F381 ◽

Cited By ~ 23

Author(s):

Greg H. Tesch ◽

Frank Y. Ma ◽

David J. Nikolic-Paterson

Keyword(s):

Kidney Disease ◽

P38 Mapk ◽

Therapeutic Potential ◽

Interstitial Fibrosis ◽

Ischemia Reperfusion ◽

Kidney Injury ◽

Upstream Regulator ◽

Jnk Inhibitors ◽

Jnk Activation ◽

Current Clinical Trial

Stress-induced activation of p38 MAPK and JNK signaling is a feature of both acute and chronic kidney disease and is associated with disease progression. Inhibitors of p38 MAPK or JNK activation provide protection against inflammation and fibrosis in animal models of kidney disease; however, clinical trials of p38 MAPK and JNK inhibitors in other diseases (rheumatoid arthritis and pulmonary fibrosis) have been disappointing. Apoptosis signal-regulating kinase 1 (ASK1) acts as an upstream regulator for the activation of p38 MAPK and JNK in kidney disease. Mice lacking the Ask1 gene are healthy with normal homeostatic functions and are protected from acute kidney injury induced by ischemia-reperfusion and from renal interstitial fibrosis induced by ureteric obstruction. Recent studies have shown that a selective ASK1 inhibitor substantially reduced renal p38 MAPK activation and halted the progression of nephropathy in diabetic mice, and this has led to a current clinical trial of an ASK1 inhibitor in patients with stage 3 or 4 diabetic kidney disease. This review explores the rationale for targeting ASK1 in kidney disease and the therapeutic potential of ASK1 inhibitors based on current experimental evidence.

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Kidney Damage Caused by Obesity and Its Feasible Treatment Drugs

International Journal of Molecular Sciences ◽

10.3390/ijms23020747 ◽

2022 ◽

Vol 23 (2) ◽

pp. 747

Author(s):

Meihui Wang ◽

Zixu Wang ◽

Yaoxing Chen ◽

Yulan Dong

Keyword(s):

Chronic Kidney Disease ◽

Kidney Disease ◽

Therapeutic Potential ◽

Kidney Injury ◽

Strong Relationship ◽

Kidney Damage ◽

Major Health Problem ◽

Major Health ◽

Lipid Metabolism Disorders ◽

Prevalence Of Obesity

The rapid growth of obesity worldwide has made it a major health problem, while the dramatic increase in the prevalence of obesity has had a significant impact on the magnitude of chronic kidney disease (CKD), especially in developing countries. A vast amount of researchers have reported a strong relationship between obesity and chronic kidney disease, and obesity can serve as an independent risk factor for kidney disease. The histological changes of kidneys in obesity-induced renal injury include glomerular or tubular hypertrophy, focal segmental glomerulosclerosis or bulbous sclerosis. Furthermore, inflammation, renal hemodynamic changes, insulin resistance and lipid metabolism disorders are all involved in the development and progression of obesity-induced nephropathy. However, there is no targeted treatment for obesity-related kidney disease. In this review, RAS inhibitors, SGLT2 inhibitors and melatonin would be presented to treat obesity-induced kidney injury. Furthermore, we concluded that melatonin can protect the kidney damage caused by obesity by inhibiting inflammation and oxidative stress, revealing its therapeutic potential.

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Artemether ameliorates kidney injury by restoring redox imbalance and improving mitochondrial function in Adriamycin nephropathy in mice

Scientific Reports ◽

10.1038/s41598-020-80298-x ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Pengxun Han ◽

Yuchun Cai ◽

Yao Wang ◽

Wenci Weng ◽

Yinghui Chen ◽

...

Keyword(s):

Kidney Disease ◽

Mitochondrial Function ◽

Biological Effects ◽

Kidney Injury ◽

High Energy ◽

Redox Imbalance ◽

Renal Tubular Cells ◽

Adriamycin Nephropathy ◽

Renal Tubular ◽

Tgf Β1

AbstractThe kidney is a high-energy demand organ rich in mitochondria especially renal tubular cells. Emerging evidence suggests that mitochondrial dysfunction, redox imbalance and kidney injury are interconnected. Artemether has biological effects by targeting mitochondria and exhibits potential therapeutic value for kidney disease. However, the underlying molecular mechanisms have not been fully elucidated. This study was performed to determine the effects of artemether on Adriamycin-induced nephropathy and the potential mechanisms were also investigated. In vivo, an Adriamycin nephropathy mouse model was established, and mice were treated with or without artemether for 2 weeks. In vitro, NRK-52E cells were stimulated with TGF-β1 and treated with or without artemether for 24 h. Then renal damage and cell changes were evaluated. The results demonstrated that artemether reduced urinary protein excretion, recovered podocyte alterations, attenuated pathological changes and alleviated renal tubular injury. Artemether also downregulated TGF-β1 mRNA expression levels, inhibited tubular proliferation, restored tubular cell phenotypes and suppressed proliferation-related signalling pathways. In addition, artemether restored renal redox imbalance, increased mtDNA copy number and improved mitochondrial function. In summary, we provided initial evidence that artemether ameliorates kidney injury by restoring redox imbalance and improving mitochondrial function in Adriamycin nephropathy in mice. Artemether may be a promising agent for the treatment kidney disease.

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Mitophagy in Acute Kidney Injury and Kidney Repair

Cells ◽

10.3390/cells9020338 ◽

2020 ◽

Vol 9 (2) ◽

pp. 338 ◽

Cited By ~ 14

Author(s):

Ying Wang ◽

Juan Cai ◽

Chengyuan Tang ◽

Zheng Dong

Keyword(s):

Acute Kidney Injury ◽

Kidney Disease ◽

Molecular Mechanisms ◽

Therapeutic Potential ◽

Kidney Injury ◽

Future Research ◽

Rapid Decline ◽

Renal Tubules ◽

Renal Tubular Cells

Acute kidney injury (AKI) is a major kidney disease characterized by rapid decline of renal function. Besides its acute consequence of high mortality, AKI has recently been recognized as an independent risk factor for chronic kidney disease (CKD). Maladaptive or incomplete repair of renal tubules after severe or episodic AKI leads to renal fibrosis and, eventually, CKD. Recent studies highlight a key role of mitochondrial pathology in AKI development and abnormal kidney repair after AKI. As such, timely elimination of damaged mitochondria in renal tubular cells represents an important quality control mechanism for cell homeostasis and survival during kidney injury and repair. Mitophagy is a selective form of autophagy that selectively removes redundant or damaged mitochondria. Here, we summarize our recent understanding on the molecular mechanisms of mitophagy, discuss the role of mitophagy in AKI development and kidney repair after AKI, and present future research directions and therapeutic potential.

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The Role of M2 Macrophages in the Progression of Chronic Kidney Disease following Acute Kidney Injury

PLoS ONE ◽

10.1371/journal.pone.0143961 ◽

2015 ◽

Vol 10 (12) ◽

pp. e0143961 ◽

Cited By ~ 59

Author(s):

Myung-Gyu Kim ◽

Sun Chul Kim ◽

Yoon Sook Ko ◽

Hee Young Lee ◽

Sang-Kyung Jo ◽

...

Keyword(s):

Chronic Kidney Disease ◽

Acute Kidney Injury ◽

Kidney Disease ◽

Kidney Injury ◽

M2 Macrophages

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Liraglutide protects against high-fat diet-induced kidney injury by ameliorating apoptosis

Endocrine Connections ◽

10.1530/ec-20-0294 ◽

2020 ◽

Vol 9 (9) ◽

pp. 946-954

Author(s):

Riying Liang ◽

Meijun Wang ◽

Chang Fu ◽

Hua Liang ◽

Hongrong Deng ◽

...

Keyword(s):

Kidney Disease ◽

High Fat Diet ◽

Mesangial Cells ◽

Morphological Changes ◽

Kidney Injury ◽

Sirtuin 1 ◽

High Fat ◽

Interacting Protein ◽

Urine Albumin ◽

Glucagon Like Peptide 1

Background: Obesity is associated with the development and progression of chronic kidney disease. Emerging evidence suggests that glucagon-like peptide-1 receptor agonist could reduce renal damage and albuminuria. Sirtuin 1 (SIRT1) was considered as a crucial regulator in metabolism-related kidney disease. Herein, the role of SIRT1 in liraglutide-ameliorated high-fat diet (HFD)-induced kidney injury was illustrated. Methods: Male C57BL/6 mice were fed HFD for 20 weeks to induce kidney injury that was then treated with liraglutide for 8 weeks to estimate its protective effect on the kidney. Also, the mechanism of the drug in SV40 MES 13 (SV40) mouse mesangial cells was elucidated. Results: Liraglutide treatment ameliorated HFD-induced metabolic disorders, including hyperglycemia, increasing body weight, and insulin resistance. In addition, kidney weight, urine albumin-to-creatinine, and kidney morphological changes such as vacuolated tubules, glomerulomegaly, thickened glomerular basement membrane, and tubulointerstitial fibrosis were also significantly ameliorated. Furthermore, apoptotic cells and apoptosis markers were downregulated in the kidney of liraglutide-treated mice. In addition, the expression of SIRT1 protein was upregulated, whereas thioredoxin-interacting protein (TXNIP), which serves as a mediator of oxidative stress and apoptosis in metabolism disease, was downregulated by liraglutide. In SV40 cells, the effect of liraglutide on reversing the upregulation of cleaved caspase-3 induced by high glucose (30 mM) was hampered when SIRT1 was knocked down; also, the downregulation of TXNIP by liraglutide was blocked. Conclusions: Liraglutide might have a beneficial effect on metabolism-related kidney damage by inhibiting apoptosis via activation of SIRT1 and suppression of TXNIP pathway.

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Mesenchymal Stem Cells as Therapeutic Agents and Novel Carriers for the Delivery of Candidate Genes in Acute Kidney Injury

Stem Cells International ◽

10.1155/2020/8875554 ◽

2020 ◽

Vol 2020 ◽

pp. 1-10

Author(s):

Yuxiang Liu ◽

Jingai Fang

Keyword(s):

Stem Cells ◽

Acute Kidney Injury ◽

Mesenchymal Stem Cells ◽

Genetic Modification ◽

Therapeutic Potential ◽

Kidney Injury ◽

Tubular Epithelial Cell ◽

Great Promise ◽

Pharmaceutical Treatment ◽

Therapeutic Outcomes

Acute kidney injury (AKI) is a heterogeneous syndrome characterized by a dramatic increase in serum creatinine. Mild AKI may merely be confined to kidney damage and resolve within days; however, severe AKI commonly involves extrarenal organ dysfunction and is associated with high mortality. There is no specific pharmaceutical treatment currently available that can reverse the course of this disease. Notably, mesenchymal stem cells (MSCs) show great promise for the management of AKI by targeting multiple pathophysiological pathways to facilitate tubular epithelial cell repair. It has been well established that the unique characteristics of MSCs make them ideal vectors for gene therapy. Thus, genetic modification has been attempted to achieve improved therapeutic outcomes in the management of AKI by overexpressing trophic cytokines or facilitating MSC delivery to renal tissues. The present article provides a comprehensive review of genetic modification strategies targeted at optimizing the therapeutic potential of MSCs in AKI.

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Regeneration and Diagnosis of Kidney Disease Using Exosomes

Jentashapir Journal of Cellular and Molecular Biology ◽

10.5812/jjcmb.120113 ◽

2021 ◽

Vol In Press (In Press) ◽

Author(s):

Leila Taghizadeh Momen ◽

Arash Abdolmaleki ◽

Asadollah Asadi ◽

Muhammad Akram

Keyword(s):

Stem Cell ◽

Kidney Disease ◽

Transmission Loss ◽

Morphological Changes ◽

Kidney Injury ◽

Bilayer Membrane ◽

Pathogen Transmission ◽

Biologically Active ◽

Immune Rejection ◽

Isolation Techniques

: A growing global prevalence of acute kidney injury (AKI) and chronic kidney disease (CKD), high costs of kidney transplantation, a shortage of kidney donors, and low survival rate after dialysis have popularized mesenchymal stem cell (MSC) therapy via transplantation. However, the risks of tumorigenesis, immune rejection, pathogen transmission, loss of differentiation, and morphological changes after long-term culture have prompted researchers to develop a safer and more effective therapy method. Therefore, cell-free approaches have been developed to reduce the risks associated with stem cell-based therapies. In cell-free therapy of AKI and CKD, MSC-derived extracellular vesicles, with nanometer sizes, are used, called exosomes. Exosomes have a lipid bilayer membrane with various genes, microRNAs, and proteins for kidney repair. As known, MSC-derived exosomes have improved the kidney regeneration process for various reasons, such as increased safety and reduced inflammation, immune rejection, and tumorigenesis. With the advancement of exosome isolation techniques, the possibility of using biologically active molecules for renal injury prediction and diagnosis has emerged. The use of urinary exosomes in AKI and CKD diagnosis is based on changes in the expression of specific molecule cargos of exosomes. This review article summarizes the diagnosis and therapeutic applications of exosomes in AKI and CKD.

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