ASK1: a new therapeutic target for kidney disease

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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Macrophage-specific deletion of transforming growth factor-β1 does not prevent renal fibrosis after severe ischemia-reperfusion or obstructive injury

AJP Renal Physiology ◽

10.1152/ajprenal.00624.2012 ◽

2013 ◽

Vol 305 (4) ◽

pp. F477-F484 ◽

Cited By ~ 40

Author(s):

Sarah C. Huen ◽

Gilbert W. Moeckel ◽

Lloyd G. Cantley

Keyword(s):

Growth Factor ◽

Kidney Disease ◽

Renal Fibrosis ◽

Transforming Growth Factor ◽

Interstitial Fibrosis ◽

Ischemia Reperfusion ◽

Kidney Injury ◽

Transforming Growth Factor Β1 ◽

Late Time ◽

Tgf Β1

Macrophage infiltration is a prominent feature of the innate immune response to kidney injury. The persistence of macrophages is associated with tubulointerstitial fibrosis and progression of chronic kidney disease. Macrophages are known to be major producers of transforming growth factor-β1 (TGF-β1), especially in the setting of phagocytosis of apoptotic cells. TGF-β1 has long been implicated as a central mediator of tissue scarring and fibrosis in many organ disease models, including kidney disease. In this study, we show that homozygous deletion of Tgfb1 in myeloid lineage cells in mice heterozygous for Tgfb1 significantly reduces kidney Tgfb1 mRNA expression and Smad activation at late time points after renal ischemia-reperfusion injury. However, this reduction in kidney Tgfb1 expression and signaling results in only a modest reduction of isolated fibrosis markers and does not lead to decreased interstitial fibrosis in either ischemic or obstructive injury models. Thus, targeting macrophage-derived TGF-β1 does not appear to be an effective therapy for attenuating progressive renal fibrosis after kidney injury.

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Cyclophilin Inhibition Protects Against Experimental Acute Kidney Injury and Renal Interstitial Fibrosis

International Journal of Molecular Sciences ◽

10.3390/ijms22010271 ◽

2020 ◽

Vol 22 (1) ◽

pp. 271

Author(s):

Khai Gene Leong ◽

Elyce Ozols ◽

John Kanellis ◽

Shawn S. Badal ◽

John T. Liles ◽

...

Keyword(s):

Acute Kidney Injury ◽

Cell Death ◽

Renal Fibrosis ◽

Ischemia Reperfusion Injury ◽

Therapeutic Potential ◽

Tissue Injury ◽

Interstitial Fibrosis ◽

Ischemia Reperfusion ◽

Kidney Injury ◽

Tubular Cell

Cyclophilins have important homeostatic roles, but following tissue injury, cyclophilin A (CypA) can promote leukocyte recruitment and inflammation, while CypD can facilitate mitochondrial-dependent cell death. This study investigated the therapeutic potential of a selective cyclophilin inhibitor (GS-642362), which does not block calcineurin function, in mouse models of tubular cell necrosis and renal fibrosis. Mice underwent bilateral renal ischemia/reperfusion injury (IRI) and were killed 24 h later: treatment with 10 or 30 mg/kg/BID GS-642362 (or vehicle) began 1 h before surgery. In the second model, mice underwent unilateral ureteric obstruction (UUO) surgery and were killed 7 days later; treatment with 10 or 30 mg/kg/BID GS-642362 (or vehicle) began 1 h before surgery. GS-642362 treatment gave a profound and dose-dependent protection from acute renal failure in the IRI model. This protection was associated with reduced tubular cell death, including a dramatic reduction in neutrophil infiltration. In the UUO model, GS-642362 treatment significantly reduced tubular cell death, macrophage infiltration, and renal fibrosis. This protective effect was independent of the upregulation of IL-2 and activation of the stress-activated protein kinases (p38 and JNK). In conclusion, GS-642362 was effective in suppressing both acute kidney injury and renal fibrosis. These findings support further investigation of cyclophilin blockade in other types of acute and chronic kidney disease.

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Targeting Ferroptosis Attenuates Interstitial Inflammation and Kidney Fibrosis

Kidney Diseases ◽

10.1159/000517723 ◽

2021 ◽

pp. 1-15

Author(s):

Lu Zhou ◽

Xian Xue ◽

Qing Hou ◽

Chunsun Dai

Keyword(s):

Mouse Models ◽

Ischemia Reperfusion Injury ◽

Interstitial Fibrosis ◽

Ischemia Reperfusion ◽

Kidney Injury ◽

Tubular Epithelial Cell ◽

Kidney Fibrosis ◽

Ureter Obstruction ◽

Regulated Necrosis ◽

Dependent Form

Background: Ferroptosis, an iron-dependent form of regulated necrosis mediated by lipid peroxidation, predominantly polyunsaturated fatty acids, is involved in postischemic and toxic kidney injury. However, the role and mechanisms for tubular epithelial cell (TEC) ferroptosis in kidney fibrosis remain largely unknown. Objectives: The aim of the study was to decipher the role and mechanisms for TEC ferroptosis in kidney fibrosis. Methods: Mouse models with unilateral ureter obstruction (UUO) or ischemia/reperfusion injury (IRI) were generated. Results: We found that TEC ferroptosis exhibited as reduced glutathione peroxidase 4 (GPX4) expression and increased 4-hydroxynonenal abundance was appeared in kidneys from chronic kidney disease (CKD) patients and mouse models with UUO or IRI. Inhibition of ferroptosis could largely mitigate kidney injury, interstitial fibrosis, and inflammatory cell accumulation in mice after UUO or IRI. Additionally, treatment of TECs with (1S,3R)-RSL-3, an inhibitor of GPX4, could enhance cell ferroptosis and recruit macrophages. Furthermore, inhibiting TEC ferroptosis reduced monocyte chemotactic protein 1 (MCP-1) secretion and macrophage chemotaxis. Conclusions: This study uncovers that TEC ferroptosis may promote interstitial fibrosis and inflammation, and targeting ferroptosis may shine a light on protecting against kidney fibrosis in patients with CKDs.

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Cellular Mechanisms of Tissue Fibrosis. 3. Novel mechanisms of kidney fibrosis

AJP Cell Physiology ◽

10.1152/ajpcell.00414.2012 ◽

2013 ◽

Vol 304 (7) ◽

pp. C591-C603 ◽

Cited By ~ 105

Author(s):

Gabriela Campanholle ◽

Giovanni Ligresti ◽

Sina A. Gharib ◽

Jeremy S. Duffield

Keyword(s):

Chronic Kidney Disease ◽

Kidney Disease ◽

Interstitial Fibrosis ◽

Kidney Injury ◽

Innate Immune ◽

Cellular Mechanisms ◽

Tubular Atrophy ◽

Kidney Fibrosis ◽

Capillary Rarefaction ◽

Peritubular Capillaries

Chronic kidney disease, defined as loss of kidney function for more than three months, is characterized pathologically by glomerulosclerosis, interstitial fibrosis, tubular atrophy, peritubular capillary rarefaction, and inflammation. Recent studies have identified a previously poorly appreciated, yet extensive population of mesenchymal cells, called either pericytes when attached to peritubular capillaries or resident fibroblasts when embedded in matrix, as the progenitors of scar-forming cells known as myofibroblasts. In response to sustained kidney injury, pericytes detach from the vasculature and differentiate into myofibroblasts, a process not only causing fibrosis, but also directly contributing to capillary rarefaction and inflammation. The interrelationship of these three detrimental processes makes myofibroblasts and their pericyte progenitors an attractive target in chronic kidney disease. In this review, we describe current understanding of the mechanisms of pericyte-to-myofibroblast differentiation during chronic kidney disease, draw parallels with disease processes in the glomerulus, and highlight promising new therapeutic strategies that target pericytes or myofibroblasts. In addition, we describe the critical paracrine roles of epithelial, endothelial, and innate immune cells in the fibrogenic process.

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The determinants, biomarkers, and consequences of microvascular injury in kidney transplant recipients

AJP Renal Physiology ◽

10.1152/ajprenal.00163.2018 ◽

2019 ◽

Vol 316 (1) ◽

pp. F9-F19 ◽

Cited By ~ 1

Author(s):

Alice Doreille ◽

Mélanie Dieudé ◽

Heloise Cardinal

Keyword(s):

Kidney Disease ◽

Kidney Transplant ◽

Interstitial Fibrosis ◽

Ischemia Reperfusion ◽

Transplant Recipients ◽

Kidney Transplant Recipients ◽

Hla Antibodies ◽

Microvascular Injury ◽

Antibody Mediated Rejection ◽

Peritubular Capillaries

Independent of the initial cause of kidney disease, microvascular injury to the peritubular capillary network appears to play a central role in the development of interstitial fibrosis in both native and transplanted kidney disease. This association is explained by mechanisms such as the upregulation of profibrotic genes and epigenetic changes induced by hypoxia, capillary leakage, endothelial and pericyte transition to interstitial fibroblasts, as well as modifications in the secretome of endothelial cells. Alloimmune injury due to antibody-mediated rejection and ischemia-reperfusion injury are the two main etiologies of microvascular damage in kidney transplant recipients. The presence of circulating donor-specific anti-human leukocyte antigen (HLA) antibodies, histological findings, such as diffuse C4d staining in peritubular capillaries, and the extent and severity of peritubular capillaritis, are commonly used clinically to provide both diagnostic and prognostic information. Complement-dependent assays, circulating non-HLA antibodies, or evaluation of the microvasculature with novel imaging techniques are the subject of ongoing studies.

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The Immunomodulatory Effect of the Gut Microbiota in Kidney Disease

Journal of Immunology Research ◽

10.1155/2021/5516035 ◽

2021 ◽

Vol 2021 ◽

pp. 1-16

Author(s):

Mingxuan Chi ◽

Kuai Ma ◽

Jing Wang ◽

Zhaolun Ding ◽

Yunlong Li ◽

...

Keyword(s):

Kidney Disease ◽

Gut Microbiota ◽

Intestinal Microbiota ◽

Ischemia Reperfusion Injury ◽

Therapeutic Potential ◽

Kidney Diseases ◽

Ischemia Reperfusion ◽

Intestinal Flora ◽

Inflammatory Factors ◽

Renal Diseases

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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Roles of Nrf2 in Protecting the Kidney from Oxidative Damage

International Journal of Molecular Sciences ◽

10.3390/ijms21082951 ◽

2020 ◽

Vol 21 (8) ◽

pp. 2951 ◽

Cited By ~ 8

Author(s):

Masahiro Nezu ◽

Norio Suzuki

Keyword(s):

Oxidative Stress ◽

Kidney Disease ◽

Ischemia Reperfusion Injury ◽

Interstitial Fibrosis ◽

Ischemia Reperfusion ◽

Organ Damage ◽

Tubular Damage ◽

Renal Tubules ◽

Renal Vasculature ◽

Nrf2 Activation

Over 10% of the global population suffers from kidney disease. However, only kidney replacement therapies, which burden medical expenses, are currently effective in treating kidney disease. Therefore, elucidating the complicated molecular pathology of kidney disease is an urgent priority for developing innovative therapeutics for kidney disease. Recent studies demonstrated that intertwined renal vasculature often causes ischemia-reperfusion injury (IRI), which generates oxidative stress, and that the accumulation of oxidative stress is a common pathway underlying various types of kidney disease. We reported that activating the antioxidative transcription factor Nrf2 in renal tubules in mice with renal IRI effectively mitigates tubular damage and interstitial fibrosis by inducing the expression of genes related to cytoprotection against oxidative stress. Additionally, since the kidney performs multiple functions beyond blood purification, renoprotection by Nrf2 activation is anticipated to lead to various benefits. Indeed, our experiments indicated the possibility that Nrf2 activation mitigates anemia, which is caused by impaired production of the erythroid growth factor erythropoietin from injured kidneys, and moderates organ damage worsened by anemic hypoxia. Clinical trials investigating Nrf2-activating compounds in kidney disease patients are ongoing, and beneficial effects are being obtained. Thus, Nrf2 activators are expected to emerge as first-in-class innovative medicine for kidney disease treatment.

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Clinical Applications of Mesenchymal Stem/Stromal Cell Derived Extracellular Vesicles: Therapeutic Potential of an Acellular Product

Diagnostics ◽

10.3390/diagnostics10120999 ◽

2020 ◽

Vol 10 (12) ◽

pp. 999

Author(s):

Margherita Massa ◽

Stefania Croce ◽

Rita Campanelli ◽

Carlotta Abbà ◽

Elisa Lenta ◽

...

Keyword(s):

Extracellular Vesicles ◽

Large Scale ◽

Therapeutic Potential ◽

Ischemia Reperfusion ◽

Clinical Stage ◽

Kidney Injury ◽

Scale Production ◽

Bioactive Lipids ◽

Anti Inflammatory ◽

Signaling Receptors

In the last decade, the secreting activity of mesenchymal stem/stromal cells (MSCs) has been widely investigated, due to its possible therapeutic role. In fact, MSCs release extracellular vesicles (EVs) containing relevant biomolecules such as mRNAs, microRNAs, bioactive lipids, and signaling receptors, able to restore physiological conditions where regenerative or anti-inflammatory actions are needed. An actual advantage would come from the therapeutic use of EVs with respect to MSCs, avoiding the possible immune rejection, the lung entrapment, improving the safety, and allowing the crossing of biological barriers. A number of concerns still have to be solved regarding the mechanisms determining the beneficial effect of MSC-EVs, the possible alteration of their properties as a consequence of the isolation/purification methods, and/or the best approach for a large-scale production for clinical use. Most of the preclinical studies have been successful, reporting for MSC-EVs a protecting role in acute kidney injury following ischemia reperfusion, a potent anti-inflammatory and anti-fibrotic effects by reducing disease associated inflammation and fibrosis in lung and liver, and the modulation of both innate and adaptive immune responses in graft versus host disease (GVHD) as well as autoimmune diseases. However, the translation of MSC-EVs to the clinical stage is still at the initial phase. Herein, we discuss the therapeutic potential of an acellular product such as MSC derived EVs (MSC-EVs) in acute and chronic pathologies.

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

AJP Renal Physiology ◽

10.1152/ajprenal.00538.2017 ◽

2018 ◽

Vol 314 (4) ◽

pp. F561-F571 ◽

Cited By ~ 4

Author(s):

Qi Cao ◽

Yiping Wang ◽

Changqi Wang ◽

Xin M. Wang ◽

Vincent W. S. Lee ◽

...

Keyword(s):

Kidney Disease ◽

Therapeutic Potential ◽

Morphological Changes ◽

Kidney Injury ◽

Peritoneal Macrophages ◽

Great Promise ◽

M2 Macrophages ◽

Peritoneal Dialysate ◽

Adriamycin Nephropathy ◽

M2 Phenotype

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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Intermittent hypoxia exacerbates increased blood pressure in rats with chronic kidney disease

AJP Renal Physiology ◽

10.1152/ajprenal.00420.2017 ◽

2018 ◽

Vol 315 (4) ◽

pp. F927-F941 ◽

Cited By ~ 3

Author(s):

Jennifer L. Riggs ◽

Carolyn E. Pace ◽

Heather H. Ward ◽

Laura V. Gonzalez Bosc ◽

Lynnette Rios ◽

...

Keyword(s):

Blood Pressure ◽

Chronic Kidney Disease ◽

Kidney Disease ◽

Intermittent Hypoxia ◽

Interstitial Fibrosis ◽

Control Diet ◽

Kidney Injury ◽

Kidney Damage ◽

Plasma Creatinine ◽

Sprague Dawley

Kidney injury and sleep apnea (SA) are independent risk factors for hypertension. Exposing rats to intermittent hypoxia (IH) to simulate SA increases blood pressure whereas adenine feeding causes persistent kidney damage to model chronic kidney disease (CKD). We hypothesized that exposing CKD rats to IH would exacerbate the development of hypertension and renal failure. Male Sprague-Dawley rats were fed a 0.2% adenine diet or control diet (Control) until blood urea nitrogen was >120 mg/dl in adenine-fed rats (14 ± 4 days, mean ± SE). After 2 wk of recovery on normal chow, rats were exposed to IH (20 exposures/h of 5% O2-5% CO2 7 h/day) or control conditions (Air) for 6 wk. Mean arterial pressure (MAP) was monitored with telemeters, and plasma and urine samples were collected weekly to calculate creatinine clearance as an index of glomerular filtration rate (GFR). Prior to IH, adenine-fed rats had higher blood pressure than rats on control diet. IH treatment increased MAP in both groups, and after 6 wk, MAP levels in the CKD/IH rats were greater than those in the CKD/Air and Control/IH rats. MAP levels in the Control/Air rats were lower than those in the other three groups. Kidney histology revealed crystalline deposits, tubule dilation, and interstitial fibrosis in both CKD groups. IH caused no additional kidney damage. Plasma creatinine was similarly increased in both CKD groups throughout whereas IH alone increased plasma creatinine. IH increases blood pressure further in CKD rats without augmenting declines in GFR but appears to impair GFR in healthy rats. We speculate that treating SA might decrease hypertension development in CKD patients and protect renal function in SA patients.

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