Macrophage-Mediated Renal Injury Is Dependent on Signaling via the JNK Pathway

Ikezumi, Yohei; L, Hurst; Atkins, Robert C.; Nikolic-Paterson, David J.

doi:10.1097/01.asn.0000131272.06958.de

Cited by 52 publications

(38 citation statements)

References 38 publications

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“…40 Another report showed that proteinuria and glomerular cell proliferation induced by anti-GBM was dependent on JNK activity in bone marrow macrophages. 44 Taken together, the present study and the previous reports support the hypothesis that loss of ABIN1 K63 and linear polyubiquitin binding leading to increased NF-kB and MAPK activity participates in the development of SLE and LN. Variants in the ABIN1 gene TNIP1 have been reported in patients with SLE, suggesting a role for ABIN1 in human autoimmune disease.…”

supporting

confidence: 75%

“…26 A role for enhanced MAPK signaling in the development of GN has been suggested in several reports. [40][41][42][43][44] Stambe et al showed enhanced active p-p38 MAPK in glomeruli, tubules, and myofibroblast and infiltrated neutrophils and macrophage in kidney biopsy specimens from patients with different types of proliferative GN, including class III/IV LN, and found that elevated p-p38 MAPK correlated with renal dysfunction and histopathology. 41 The same group showed in a separate study that administration of a specific p38 MAPK inhibitor prevented renal injury and renal function loss from anti-glomerular basement membrane (GBM)-induced GN in rats.…”

mentioning

confidence: 99%

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ABIN1 Dysfunction as a Genetic Basis for Lupus Nephritis

Caster¹,

Korte²,

Nanda

et al. 2013

Journal of the American Society of Nephrology

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The genetic factors underlying the pathogenesis of lupus nephritis associated with systemic lupus erythematosus are largely unknown, although animal studies indicate that nuclear factor (NF)-kB is involved. We reported previously that a knockin mouse expressing an inactive form of ABIN1 (ABIN1[D485N]) develops lupus-like autoimmune disease and demonstrates enhanced activation of NF-kB and mitogen-activated protein kinases in immune cells after toll-like receptor stimulation. In the current study, we show that ABIN1[D485N] mice develop progressive GN similar to class III and IV lupus nephritis in humans. To investigate the clinical relevance of ABIN1 dysfunction, we genotyped five single-nucleotide polymorphisms in the gene encoding ABIN1, TNIP1, in samples from European-American, African American, Asian, Gullah, and Hispanic participants in the Large Lupus Association Study 2. Comparing cases of systemic lupus erythematosus with nephritis and cases of systemic lupus erythematosus without nephritis revealed strong associations with lupus nephritis at rs7708392 in European Americans and rs4958881 in African Americans. Comparing cases of systemic lupus erythematosus with nephritis and healthy controls revealed a stronger association at rs7708392 in European Americans but not at rs4958881 in African Americans. Our data suggest that variants in the TNIP1 gene are associated with the risk for lupus nephritis and could be mechanistically involved in disease development via aberrant regulation of NF-kB and mitogen-activated protein kinase activity. 24: 174324: -175424: , 201324: . doi: 10.1681 Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease characterized by an abnormal immune response leading to autoantibody production, immune complex formation, T cell activation, and inflammatory cytokine release. 1 Multiple factors contribute to the immune response in SLE, including genetic, epigenetic, immunoregulatory, environmental, and hormonal factors. 1 Lupus nephritis (LN) occurs in about 50% of patients with SLE and is a major cause of morbidity and mortality. 2 The incidence of LN varies among different ethnic groups, suggesting that genetic factors play an important role in the pathogenesis. Patients with African ancestry are at Received February 11, 2013. Accepted May 7, 2013 D.J.C. and E.A.K. contributed equally to this work. J Am Soc NephrolPublished online ahead of print. Publication date available at www.jasn.org. LN,4 and that therapy is associated with undesirable short-and long-term adverse effects. Thus, identifying the molecular mechanisms responsible for the pathogenesis of LN is necessary to define more specific diagnostic and therapeutic targets. However, the complex interactions of genetic risks, environmental factors, and molecular events that contribute to the development of LN are only beginning to be defined. The transcription factor nuclear factor-kB (NF-kB) regulates the expression of hundreds of genes that control cell proliferation and survival, the cellular stress r...

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supporting

confidence: 75%

mentioning

confidence: 99%

ABIN1 Dysfunction as a Genetic Basis for Lupus Nephritis

Caster¹,

Korte²,

Nanda

et al. 2013

Journal of the American Society of Nephrology

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“…Macrophages also have been postulated as mediators of tubular epithelial cell apoptosis (51). CC-401 treatment had no effect on interstitial macrophage accumulation in the obstructed kidney; however, we cannot rule out that JNK signaling may have a role in macrophage activation that leads to tubular epithelial cell apoptosis in the UUO model, because previous adoptive transfer studies in rat anti-glomerular basement membrane disease have shown that blockade of JNK signaling in macrophages can reduce substantially macrophage-mediated renal injury without any effect on macrophage recruitment into the injured kidney (52).…”

Section: Discussionmentioning

confidence: 89%

A Pathogenic Role for c-Jun Amino-Terminal Kinase Signaling in Renal Fibrosis and Tubular Cell Apoptosis

Ma¹,

Flanc²,

Tesch³

et al. 2007

Journal of the American Society of Nephrology

161

139

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Renal fibrosis and tubular apoptosis are common mechanisms of progressive kidney disease. In vitro studies have implicated the c-Jun amino-terminal kinase (JNK) pathway in these processes. Both of the major JNK isoforms, JNK1 and JNK2, are expressed in the kidney, but their relative contribution to JNK signaling is unknown. This study investigated the role of JNK signaling in renal fibrosis and tubular apoptosis in the unilateral ureteral obstruction model using two different approaches: (1) Mice that were deficient in either JNK1 or JNK2 and (2) a specific inhibitor of all JNK isoforms, CC-401. Western blotting and immunostaining identified a marked increase in JNK signaling in the obstructed kidney, with substantial redundancy between JNK1 and JNK2 isoforms. Administration of CC-401 blocked JNK signaling in the rat obstructed kidney and significantly inhibited renal fibrosis in terms of interstitial myofibroblast accumulation and collagen IV deposition. This effect was attributed to suppression of gene transcription for the profibrotic molecules TGF-␤1 and connective tissue growth factor. CC-401 treatment also significantly reduced tubular apoptosis in the obstructed kidney. Genetic deletion of JNK1 or JNK2 did not protect mice from renal fibrosis in the unilateral ureteral obstruction model, but JNK1 deletion did result in a significant reduction in tubular cell apoptosis. In conclusion, this is the first study to demonstrate that JNK signaling plays a pathogenic role in renal fibrosis and tubular apoptosis. Furthermore, JNK1 plays a nonredundant role in tubular cell apoptosis. These studies identify the JNK pathway as a potential therapeutic target in progressive kidney disease.

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“…The role of JNK in macrophage-mediated renal injury in this model was addressed using an adoptive transfer approach. Administration of a JNK inhibitor to cultured macrophages before their transfer into leukocyte-depleted rats given anti-GBM serum did not prevent macrophage recruitment into glomeruli, but it profoundly inhibited the induction of proteinuria and mesangial cell proliferation indicating that the macrophage response had been modified (35). Indeed, JNK blockade markedly blunted the TNF-α response in cultured macrophages (35).…”

Section: Jnk In Glomerular Diseasementioning

confidence: 99%

The role of stress-activated protein kinase signaling in renal pathophysiology

Liu

Nikolic-Paterson

2008

Braz J Med Biol Res

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Two major stress-activated protein kinases are the p38 mitogen-activated protein kinase (MAPK) and the c-Jun amino terminal kinase (JNK). p38 and JNK are widely expressed in different cell types in various tissues and can be activated by a diverse range of stimuli. Signaling through p38 and JNK is critical for embryonic development. In adult kidney, p38 and JNK signaling is evident in a restricted pattern suggesting a normal physiological role. Marked activation of both p38 and JNK pathways occurs in human renal disease, including glomerulonephritis, diabetic nephropathy and acute renal failure. Administration of small molecule inhibitors of p38 and JNK has been shown to provide protection from renal injury in different types of experimental kidney disease through inhibition of renal inflammation, fibrosis, and apoptosis. In particular, a role for JNK signaling has been identified in macrophage activation resulting in up-regulation of pro-inflammatory mediators and the induction of renal injury. The ability to provide renal protection by blocking either p38 or JNK indicates a lack of redundancy for these two signaling pathways despite their activation by common stimuli. Therefore, the stress-activated protein kinases, p38 and JNK, are promising candidates for therapeutic intervention in human renal diseases.

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Macrophage-Mediated Renal Injury Is Dependent on Signaling via the JNK Pathway

Cited by 52 publications

References 38 publications

ABIN1 Dysfunction as a Genetic Basis for Lupus Nephritis

ABIN1 Dysfunction as a Genetic Basis for Lupus Nephritis

A Pathogenic Role for c-Jun Amino-Terminal Kinase Signaling in Renal Fibrosis and Tubular Cell Apoptosis

The role of stress-activated protein kinase signaling in renal pathophysiology

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