|
 
 |
| REVIEW ARTICLE |
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| Year : 2021 | Volume
: 8
| Issue : 1 | Page : 10 |
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JUN amino terminal kinase in cell death and inflammation in acute and chronic kidney disease
David J Nikolic-Paterson, Keren Grynberg, Frank Y Ma
Department of Nephrology, Monash Medical Centre; Monash University Centre for Inflammatory Diseases, Monash Medical Centre, Clayton, Victoria, Australia
| Date of Submission | 01-Mar-2021 |
| Date of Decision | 04-Aug-2021 |
| Date of Acceptance | 06-Aug-2021 |
| Date of Web Publication | 24-Nov-2021 |
Correspondence Address:
Prof. David J Nikolic-Paterson
Department of Nephrology, Monash Medical Centre, Clayton, Victoria 3168
Australia
 Source of Support: None, Conflict of Interest: None
DOI: 10.4103/imna.imna_35_21
Cell death and inflammation are important mechanisms in the induction of acute kidney injury (AKI) and the progression of chronic kidney disease. This focused review examines how the JUN amino terminal kinase (JNK) enzyme contributes to these pathologies. The JNK enzyme is activated in response to cellular stress, being most sensitive to oxidative stress. Biopsy studies have shown that JNK signaling is activated in human AKI and chronic kidney injury. Genetic and pharmacologic strategies have demonstrated a key role for JNK signaling in tubular cell death, inflammation, and loss of renal function in various animal models of AKI. This has been directly attributed to JNK1 signaling in the proximal tubular epithelial cells. JNK inhibition also reduces cell death, inflammation, and fibrosis in several models of progressive kidney disease; however, not all models show benefit with JNK blockade. JNK inhibitors are currently in clinical trials which opens the way for testing JNK-based therapy in selected types of renal injury. Some of the outstanding questions in this field include identifying the JNK1 target(s) in the induction of tubular cell necroptosis, and determining whether the pro-inflammatory actions of JNK signalling depend solely upon activation of JUN/Activator Protein-1.
Keywords: Acute kidney injury, activator protein-1, ischemia/reperfusion injury, JUN, JUN amino terminal kinase, necroptosis, renal fibrosis
How to cite this article:
Nikolic-Paterson DJ, Grynberg K, Ma FY. JUN amino terminal kinase in cell death and inflammation in acute and chronic kidney disease. Integr Med Nephrol Androl 2021;8:10 |
How to cite this URL:
Nikolic-Paterson DJ, Grynberg K, Ma FY. JUN amino terminal kinase in cell death and inflammation in acute and chronic kidney disease. Integr Med Nephrol Androl [serial online] 2021 [cited 2023 Mar 26];8:10. Available from: https://journal-imna.com//text.asp?2021/8/1/10/331076 |
| Introduction | |  |
Inflammation is a common response to tissue injury and plays an important role in the healing process. However, severe acute inflammation within the kidney can cause substantial injury, resulting in histologic damage and acute loss of renal function. In addition, sustained inflammation that fails to resolve is an important driver in many forms of progressive kidney disease.[1]
Pathologic cell death is intricately linked to the inflammatory response. While apoptosis is considered a noninflammatory form of programmed cell death, the various forms of necrosis are highly inflammatory. Several types of programmed necrosis have now been identified: necroptosis, ferroptosis, and pyroptosis.[2] These forms of necrosis cause cell lysis with the release of danger-associated molecular patterns (DAMPs)/alarmins and cellular organelles into the immediate extracellular microenvironment – invoking a strong inflammatory response with the rapid recruitment and activation of innate immune cells.[2],[3]
Cell death and inflammation are important mechanisms in both acute kidney injury (AKI) and chronic kidney injury. However, we have no specific therapies to target these pathologic mechanisms. Therefore, it is important to understand these processes and seek new therapeutic approaches to protect the kidney from such damage. The topic of this focus review is how the JUN amino terminal kinase (JNK) signaling pathway facilitates both cell death and inflammation in acute and chronic forms of kidney injury.
| Outline Of The Jun Amino Terminal Kinase Signaling Pathway | | |
The JNK enzyme is part of the mitogen-activated protein kinase (MAPK) family. Alternative mRNA splicing of the three Jnk genes (Mapk8/Jnk1, Mapk9/Jnk2, and Mapk10/Jnk3) gives rise to many different JNK protein isoforms.[4] JNK1 and JNK2 are widely expressed in the kidney and throughout the body, including the kidney, while JNK3 is only expressed in the heart, brain, and testis.[5]
The JNK enzyme is activated by phosphorylation in its active site by upstream kinases, MAP2K4 and MAP2K7, which in turn are activated by MAP3K enzymes [Figure 1]. DAMPs and alarmins, as well as a number of cytokines and growth factors implicated in renal inflammation and fibrosis, can activate JNK [Figure 1]. However, the most potent activators of JNK are reactive oxygen species (ROS), which can originate within the cell and from outside of the cell. | Figure 1: The JNK signaling pathway. Inflammatory cytokines, danger-associated molecular patterns and pro-fibrotic growth factors can induce phosphorylation/activation of enzymes in the MAP3K family. MAP3K enzymes then activate MAP2K4 and MAP2K7 which directly phosphorylate and active JNK. In addition, JNK is highly susceptible to activation by ROS; this operates via ROS activation of MAP3K5. Activated JNK can induce cell apoptosis by causing cytochrome c release by mitochondria and by necroptosis via activation of the RIPK3/MLKL pathway. In the nucleus, activated JNK can phosphorylate the amino terminus of JUN to activate the transcription factor AP1 which transcribes gene involved in the inflammatory and fibrotic responses. In addition, activated JNK can phosphorylate the linker region of SMAD3 to enhance TGF-β1-induced transcription of profibrotic factors. This diagram is reproduced with permission based on an earlier publication of the same authors.[6] JNK: JUN amino terminal kinase, MAP3K: Mitogen-activated protein kinase kinase kinase, ROS: Reactive oxygen species, RIPK3: Receptor interacting serine/threonine kinase 3, MLKL: Mixed lineage kinase domain-like pseudokinase, AP1: Activator protein 1, SMAD3: Mothers against decapentaplegic homolog 3, TGF-β1: Transforming growth factor-beta 1
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JNK can phosphorylate serine and threonine residues in a range of proteins, although many JNK target proteins are poorly defined. The name JNK is based on the phosphorylation of Serine 63 and 73 in the amino terminal of the JUN protein. Many of the proinflammatory actions of JNK signaling are presumed to be due to JUN phosphorylation, which facilitates JUN (proto-oncogene C-Jun) binding with FOS (proto-oncogene C-Fos) to form the transcription factor activator protein 1 (AP-1). There are AP-1 binding sites in the promoter regions of many genes involved in the inflammatory response (e.g., Ccl2, Nos2, and Mmp12) and the fibrotic response (e.g., Cola1a, Tgfb1, and Fn1). By contrast, JNK targets in cell death are poorly defined. Oxidative stress-induced cell apoptosis may operate via JNK-mediated phosphorylation of B-cell CLL/lymphoma 2 (BCL2) and BCL2-like 1, leading to release of cytochrome c from mitochondria, caspase-3 activation, and cell death.[7]
| Role Of Jun Amino Terminal Kinase In Acute Kidney Injury | | |
AKI is encountered in a number of clinical settings where a variety of causes (e.g., severe blood loss, major cardiac or abdominal surgery, and sepsis) result in low blood pressure and hypoperfusion of the kidney. Acute exposure to renal toxins, including some cancer treatments and drug overdose, can also induce AKI.[8] Severe AKI is associated with high mortality rates and may necessitate the need for immediate dialysis.[9] Patients with less severe AKI not requiring dialysis are still at increased risk of later developing chronic kidney disease (CKD) or exacerbation of preexisting CKD.[9],[10]
There is prominent activation/phosphorylation of JNK in the tubular epithelial cells in postperfusion biopsies of human kidney transplants, with the degree of JNK activation correlating with ischemic time in deceased donor allografts.[11] Strong induction of JNK signaling is also evident in mouse and rat models of renal ischemia/reperfusion injury (IRI).[11],[12],[13] Prophylactic treatment with small molecule JNK inhibitor drugs provides substantial protection against tubular cell necrosis, neutrophil infiltration, inflammation, and acute renal failure across mouse, rat, and porcine models of renal IRI.[11],[13],[14],[15] However, these inhibitors do not distinguish between the role of JNK1 versus JNK2 in this injury. This question was addressed by using gene-knockout mice. Jnk1-/- mice are protected against tubular necrosis, neutrophil infiltration, and acute loss of renal failure in renal IRI, whereas Jnk2-/- mice showed no protection.[15] Furthermore, conditional deletion of Jnk1 in the proximal tubular cells was sufficient to protect mice against tubular necrosis and a loss of renal function. These mice also showed a reduction in neutrophil and macrophage infiltration and a reduction in mRNA levels of inflammatory mediators Tnf, Il6, Ccl2, and Nos2:[15] this was attributed to the reduced tubular cell death and damage which results in less DAMPs and alarmins being released and thus reduces myeloid cell recruitment and activation. However, a formal study of JNK function in the myeloid cells in this model is required to address this point. Consistent with the mouse renal IRI studies; Jnk1-/- but not Jnk2-/- tubular cells were protected from ROS-induced cell death. This protection was associated with preventing activation of the receptor interacting serine/threonine kinase 3 (RIPK3)/mixed lineage kinase domain-like pseudokinase (MLKL) necroptosis pathway, providing the first direct demonstration that JNK1 is required for RIPK3/MLKL activation in a necroptosis pathway.[15]
These studies establish JNK as an important therapeutic target to prevent renal IRI. However, other approaches have emerged to target JNK signaling by focusing on upstream events. Reperfusion injury of the kidney involves excessive production of ROS. The MAP3K family member, apoptosis signal-regulated kinase-1 (ASK1/MAP3K5) is maintained in an inactive state during homeostasis through binding to the reduced form of thioredoxin; however, pathological levels of ROS can oxidize thioredoxin which then dissociates, allowing autoactivation of ASK1.[16] Activated ASK1 leads directly to activation of both JNK and p38 MAPK. Studies using Ask1 gene deletion, or an ASK1 inhibitor, show efficient blockade of JNK signaling and protection against tubule necrosis, inflammation, and loss of renal function in models of IRI, which are comparable to that seen with JNK blockade alone.[17]
AKI can also be induced by nephrotoxic drugs, such as aristolochic acid which causes Balkan nephropathy, or the chemotherapeutic drug, cisplatin. Prophylatic treatment with the JNK inhibitor, SP600125, reduced tubular cell necrosis, macrophage infiltration, and acute renal failure in cisplatin-treated rats.[18] Similarly, treatment with a different JNK inhibitor, CC-930, suppressed tubular cell necrosis and damage, macrophage infiltration, upregulation of proinflammatory cytokines (Tnf, Il36a), and renal function impairment in aristolochic acid-induced AKI in mice.[19] Thus, JNK signaling is a common mechanism whereby a variety of different kidney insults induce tubular cell necrosis and acute kidney failure.
| The Role Of Jun Amino Terminal Kinase In Chronic Kidney Disease | | |
While inflammatory necrotic cell death is often seen in AKI, this is generally not the case in CKD – other than in acute flares in some diseases such as ANCA-associated vasculitis. Cell death is still a feature of CKD, but this is usually in the form of apoptosis and the gradual loss of mesenchymal cells of the kidney – a process often associated with glomerulosclerosis and interstitial fibrosis. However, inflammation is a feature in virtually all progressive forms of CKD, including diabetic kidney disease.[1],[20]
While JNK signaling is not detectable in normal glomeruli, glomerular cells exhibiting phosphorylated/activated JNK (p-JNK) and p-JUN Ser63 are evident in most types of human glomerulonephritis and diabetic kidney disease. Glomerular JNK activation correlates with macrophage infiltration and glomerulosclerosis, but not with proteinuria or renal function.[21],[22] Animal models of glomerular disease also exhibit JNK activation in glomerular cells in models as varied as salt-sensitive hypertension, adriamycin-induced nephrosis, crescentic glomerulonephritis, diabetic nephropathy, and Alport's syndrome.[23],[24],[25],[26],[27]
Rat anti-glomerular basement membrane (GBM) glomerulonephritis is an immunologic disease featuring crescentic formation in which renal injury is mediated by macrophages.[28] Acute glomerular injury features JNK activation in infiltrating macrophages, podocytes, and crescent cells.[23] Treatment with a JNK inhibitor did not prevent glomerular macrophage infiltration, but it did suppress the M1 proinflammatory macrophage response: This was associated with the protection against proteinuria, crescent formation, and glomerulosclerosis.[23] Delaying JNK inhibitor treatment until glomerular injury and proteinuria were established was still effective in suppressing the M1 proinflammatory macrophage response (upregulation of Nos2, Tnf, Mmp9, and Mmp12) and protecting against exacerbation of proteinuria, loss of renal function, further glomerular damage, and renal fibrosis. The interpretation that macrophage-mediated glomerular injury in this model depends upon JNK signaling is supported by an adoptive transfer study. JNK inhibition in transferred macrophages did not prevent their localization within the glomerulus, but it did prevent their activation and glomerular injury.[29]
Macrophages also play a pathological role in models of type 1 and type 2 diabetic kidney disease.[30],[31],[32] However, long-term (10 weeks) JNK inhibition in models of type 1 diabetes in spontaneously hypertensive rats or in type 2 diabetes in db/db mice did not prevent mesangial expansion and resulted in a minor increase in podocyte injury and albuminuria.[24],[33] JNK inhibition did reduce glomerular macrophage infiltration,[24] but long-term JNK inhibition may be detrimental to already damaged podocytes.
Activation of the JNK pathway is much more prominent in the tubulointerstitial compartment compared to glomeruli in human glomerular diseases. Indeed, the number of p-JNK+ and p-JUN+ tubulointerstitial cells correlates with declining renal function, macrophage infiltration, tubular damage, and interstitial fibrosis.[21],[22] A similar prominent activation of JNK signaling in tubular cells is evident across most models of CKD including progressive anti-GBM disease, unilateral ureteric obstruction (UUO), and interstitial fibrosis induced by IRI, folic acid, or aristolochic acid.[12],[19],[34],[35],[36] The UUO model features tubular cell apoptosis and a rapid and aggressive interstitial fibrosis. Neither Jnk1-/- or Jnk2-/- mice were protected from UUO-induced fibrosis, although there was a significant reduction in tubular apoptosis in Jnk1-/- mice.[36] Interestingly, deletion of either Jnk1 or Jnk2 genes did not affect JUN activation; however, administration of a JNK inhibitor drug efficiently blocked JUN activation and inhibited both tubular cell apoptosis and renal interstitial fibrosis.[36] Together with the findings in the renal IRI model,[15] this indicates a distinct function for JNK1 in promoting cell death, while there is redundancy between JNK1 and JNK2 for JUN/AP-1 activation where both must be inhibited to suppress renal interstitial fibrosis.
Support for a role of JNK signaling in renal fibrosis comes from studies in other disease models. Administration of a JNK inhibitor over 7–28 days following unilateral IRI suppressed the development of renal interstitial fibrosis.[37] This was attributed to the prevention of G2/M cell cycle arrest in the tubular epithelial cells and the consequent reduction in production of profibrotic factors by such cells.[37] In a different study, mice were treated with a JNK inhibitor (SP600125), an mothers against decapentaplegic homolog 3 (SMAD3) inhibitor (SIS3), or combined treatment over 6–28 days following folic acid-induced AKI. The development of renal interstitial fibrosis and renal dysfunction was partially reduced by SP600125 and SIS3 as single treatments, without affecting the other pathway, while the combined therapy gave an additive and profound reduction in renal fibrosis.[34] This protective effect was associated with modulation of peroxisome proliferator-activated receptor gamma coactivator 1-alpha expression – a key factor regulating gene involved in mitochondrial biogenesis.[34]
In contrast to other studies, JNK inhibition with CC-930 was not effective in a model of renal interstitial fibrosis induced by chronic administration of the tubular toxin, aristolochic acid.[19] In this model, tubular damage is driven by activation of the DNA repair response and features tubular atrophy and senescence. While JNK inhibition suppressed tubular damage in response to a single high dose of aristolochic acid, the ongoing tubular damage, induction of tubular senescence, and renal fibrosis by chronic low-dose aristolochic acid exposure operated independently of JNK signaling. Interestingly, JNK signaling was prominent in atrophic and senescent tubular epithelial cells, but JNK blockade did not modify this response.[19]
| Mechanisms By Which Jun Amino Terminal Kinase Signaling Promotes Renal Fibrosis | | |
Studies of disease models and cultured cells have identified a number of mechanisms by which JNK signaling can promote renal fibrosis. First, JNK signaling can induce tubular cell necrosis and renal inflammation in AKI which indirectly leads to renal fibrosis. This operates via JNK-dependent cell necrosis as described above, as well as via JNK activation of JUN/AP-1 which induces transcription of many proinflammatory molecules – often in cooperation with other transcription factors such as nuclear factor kappa B and nuclear factor of activated T cells.[38],[39] Second, there is a functional AP-1 binding site in the promoter region of the Tgfb1 gene, and the factors such as interleukin-1, tumor necrosis factor, and angiotensin II induce Tgfb1 transcription via JNK signaling.[40],[41] In addition, transforming growth factor-beta 1 (TGF-β1) autoinduction also depends upon the JNK/AP-1 pathway.[42] Third, the JNK-JUN/AP-1 pathway promotes activation of latent TGF-β1 protein via inducing transcription of thrombospondin-1.[41] Fourth, JNK directly interacts in the profibrotic TGF-β/SMAD3 pathway.[43] JNK can phosphorylate the linker region of SMAD3, resulting in increased transcriptional activity.[44] Support for this mechanism in fibrotic disease comes from co-immunoprecipitation studies showing that active JNK binds to SMAD3 in associated with linker region phosphorylation in the UUO model of renal fibrosis.[45] Fifth, stimulation of fibroblast proliferation by TGF-β1, platelet-derived growth factor (PDGF), or aldosterone operates via JNK signaling.[46],[47],[48] In addition, the transgenic overexpression of JUN in the tubular epithelial cells results in tubular dedifferentiation, tubular atrophy, interstitial fibrosis, and loss of renal function,[49] although the relevance of this finding to human renal disease remains to be determined.
| Clinical Trials Of Jun Amino Terminal Kinase Inhibitors | | |
No trials of JNK inhibitors have been performed to date in patients with kidney disease. However, the demonstration that blockade of JNK signaling could prevent fibrosis in models of kidney, lung, and liver disease has led to clinical trials.[36],[50],[51] CC-930 was used in a phase 2 trial of patients with idiopathic pulmonary fibrosis; however, the trial was halted due to liver toxicity even though reductions in markers of lung fibrosis were noted.[51] CC-390 inhibits the kinase activity of JNK2 with 9-fold greater potency than JNK1 or JNK3.[52] A new phase 2 trial of idiopathic pulmonary fibrosis is now underway with CC-90001 (NCT03142191), a drug which preferentially inhibits JNK1 over JNK2. CC-90001 is also underway in a phase 2 trial of patients with nonalcoholic steatohepatitis and stage 3 or stage 4 liver fibrosis (NCT04048876). A different type of JNK inhibitor, a cell-permeable peptide that blocks JNK binding to the JNK interacting protein 1 (MAPK8IP1), has been shown to protect against aminoglycoside and acoustic trauma-induced auditory hair cell death and hearing loss in experimental animals.[53] This peptide, known as XG-102/AM-111/brimapitide, recently completed a phase 3 trial in patients suffering from severe to profound acute unilateral idiopathic sudden sensorineural hearing loss (ISSNHL). While the primary efficacy end point was not met in the overall study population, post hoc analysis showed a clinically relevant and nominally significant treatment effect for AM-111 in patients with profound ISSNHL.[54]
| Questions To Be Addressed | | |
There are many unanswered questions regarding how the JNK-JUN/AP-1 pathway induces cell death and inflammation in kidney disease. First, we need to identify the specific JNK1 target proteins that lead to tubular cell necroptosis in AKI. In addition, since JNK blockade does not provide complete protection against renal IRI, it is important to investigate the combination of JNK blockade with inhibitors of other types of programmed necrotic cell death to define an optimal strategy to prevent anticipated AKI. Second, while there are good data to support JNK signaling as an important driver of the M1 proinflammatory response in mediating renal injury, we lack information regarding the function of JNK signaling in other renal cell types in models of chronic kidney disease – most notably in tubular epithelial cells, fibroblasts, and podocytes. Third, a major unanswered question is whether JNK-dependent production of proinflammatory and profibrotic molecules operates solely through JUN/AP-1? The other side of this question is whether there is a significant JNK-independent role of JUN/AP-1 in renal inflammation and fibrosis? This can be answered by developing strategies for targeting JUN/AP-1 function in disease models. However, this is challenging since Jun gene deletion is fetal lethal in mice,[55] and no selective small molecule inhibitors of JUN function have been described thus far.[56] Indeed, while JNK phosphorylates the amino terminus of JUN, different kinases phosphorylate other portions of the JUN protein; thus, it is not entirely clear to what degree JNK inhibition impacts overall AP-1 function. Fourth, it is not entirely clear whether clinical treatment should focus on JNK1 versus JNK2? There are likely to be disease specific consideration, but the liver toxicity seen with CC-930 treatment in patients indicates that long-term JNK2 inhibition is to be avoided. It remains to be seen whether long-term JNK1 inhibition will be an effective strategy in patients.
Financial support and sponsorship
This work was funded by the National Health Medical Research Council of Australia (1058175 and 1156982).
Conflicts of interest
D. J.N-P. has received research funding and/or compounds from Celgene for studies of JNK inhibitors (CC-401 and CC-930) in kidney disease and research funding and/or compounds from Gilead for studies of an ASK1 inhibitor (GS-444217) in kidney disease. This author is also an associate Editor-in-Chief of the journal. The article was subject to the journal's standard procedures, with peer review handled independently of this editor and his research groups.
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