Loss of NLRP6 expression increases the severity of acute kidney injury

2019 ◽  
Vol 35 (4) ◽  
pp. 587-598 ◽  
Author(s):  
Lara Valiño-Rivas ◽  
Leticia Cuarental ◽  
Gabriel Nuñez ◽  
Ana B Sanz ◽  
Alberto Ortiz ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Messenger Rna ◽  
Kidney Injury ◽  
Human Kidney ◽  
Sterile Inflammation ◽  
Mitogen Activated Protein Kinase ◽  
Tubular Cells ◽  
Extracellular Signal ◽  
Mitogen Activated Protein ◽  
And Function

Abstract Background Nlrp6 is a nucleotide-binding oligomerization domain-like receptor (NLR) that forms atypical inflammasomes. Nlrp6 modulates the gut epithelium interaction with the microbiota. However, the expression and function of Nlrp6 in the kidney, a sterile environment, have not been characterized. We explored the role of Nlrp6 in acute kidney injury (AKI). Methods In a transcriptomics array of murine nephrotoxic AKI, Nlrp6 and Naip3 were the only significantly downregulated NLR genes. The functional implications of Nlrp6 downregulation were explored in mice and in cultured murine tubular cells. Results Nlrp6 was expressed by healthy murine and human kidney tubular epithelium, and expression was reduced during human kidney injury or murine nephrotoxic AKI induced by cisplatin or a folic acid overdose. Genetic Nlrp6 deficiency resulted in upregulation of kidney extracellular signal–regulated kinase 1/2 (ERK1/2) and p38 mitogen-activated protein kinase (MAPK) phosphorylation and more severe AKI and kidney inflammation. In cultured tubular cells, Nlrp6 downregulation induced by specific small interfering RNA resulted in upregulation of ERK1/2 and p38 phosphorylation and chemokine messenger RNA expression and downregulation of the nephroprotective gene Klotho. MAPK inhibition prevented the inflammatory response in Nlrp6-deficient cells. Conclusion Nlrp6 dampens sterile inflammation and has a nephroprotective role during nephrotoxic kidney injury through suppression of MAP kinase activation.

Platycodin D Ameliorates Acute Kidney Injury in Septic Rats by Regulating Mitogen Activated Protein Kinase Pathway

2020 ◽  
Vol 19 (3) ◽  
pp. 270-276
Author(s):  
Jianying Wang ◽  
Xiaoting Yu
Keyword(s):  
Acute Kidney Injury ◽  
Protein Kinase ◽  
Protective Effect ◽  
Cecal Ligation ◽  
Kidney Injury ◽  
B Cell Lymphoma ◽  
Mitogen Activated Protein Kinase ◽  
Cecal Ligation And Puncture ◽  
Platycodin D ◽  
Mitogen Activated Protein

Acute kidney injury is a severe complication of sepsis. We have shown a protective effect of Platycodin D on sepsis induced acute kidney injury in an animal model that employs cecal ligation and puncture. Cecal ligation and puncture induced a series of degenerative changes in kidney, such as edema, hyperemia, and expansion in glomerular capillary, and inflammatory cells infiltration that were attenuated by Platycodin D. Also, rise in proinflammatory cytokine levels in septic rats was blunted by Platycodin D. Furthermore, Platycodin D administration reduced rise in serum levels of kidney injury markers-blood urea nitrogen and serum creatinine-in septic rats. Moreover, Platycodin D administration also suppressed the cell apoptosis in kidney that was associated with enhanced B-cell lymphoma 2 protein and reduced cleaved cysteine-aspartic protease-3 and BCL2-associated X protein. Lastly, Platycodin D administration attenuated sepsis-induced increase of phospho (p)-extracellular signal-regulated kinase, p-c-Jun NH2-terminal kinase, and p-p38. In conclusion, Platycodin D demonstrated protective effect against sepsis induced acute kidney injury through inactivation of mitogen activated protein kinase pathways, thus providing promising therapeutic strategy for the treatment of sepsis.

scholarly journals Collagen/β1 integrin signaling up-regulates the ABCC1/MRP-1 transporter in an ERK/MAPK-dependent manner

2012 ◽  
Vol 23 (17) ◽  
pp. 3473-3484 ◽  
Author(s):  
Mohammed-Amine El Azreq ◽  
Dalila Naci ◽  
Fawzi Aoudjit
Keyword(s):  
Actin Polymerization ◽  
Mitogen Activated Protein Kinase ◽  
Integrin Signaling ◽  
Β1 Integrin ◽  
Dependent Manner ◽  
Expression Levels ◽  
Extracellular Signal ◽  
Mitogen Activated Protein ◽  
Induced Apoptosis ◽  
And Function

The mechanisms by which β1 integrins regulate chemoresistance of cancer cells are still poorly understood. In this study, we report that collagen/β1 integrin signaling inhibits doxorubicin-induced apoptosis of Jurkat and HSB2 leukemic T-cells by up-regulating the expression and function of the ATP-binding cassette C 1 (ABCC1) transporter, also known as multidrug resistance–associated protein 1. We find that collagen but not fibronectin reduces intracellular doxorubicin content and up-regulates the expression levels of ABCC1. Inhibition and knockdown studies show that up-regulation of ABCC1 is necessary for collagen-mediated reduction of intracellular doxorubicin content and collagen-mediated inhibition of doxorubicin-induced apoptosis. We also demonstrate that activation of the extracellular signal-regulated kinase (ERK)/mitogen-activated protein kinase signaling pathway is involved in collagen-induced reduction of intracellular doxorubicin accumulation, collagen-induced up-regulation of ABCC1 expression levels, and collagen-mediated cell survival. Finally, collagen-mediated up-regulation of ABCC1 expression and function also requires actin polymerization. Taken together, our results indicate for the first time that collagen/β1 integrin/ERK signaling up-regulates the expression and function of ABCC1 and suggest that its activation could represent an important pathway in cancer chemoresistance. Thus simultaneous targeting of collagen/β1 integrin and ABCC1 may be more efficient in preventing drug resistance than targeting each pathway alone.

Acute interstitial nephritis: New agents for an old entity

2020 ◽  
Vol 4 (3) ◽  
pp. 100-104
Author(s):  
Filipa Cardoso ◽  
Rui Barata ◽  
David Navarro ◽  
Marco Mendes ◽  
Mário Góis ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Protein Kinase ◽  
Kidney Function ◽  
Interstitial Nephritis ◽  
Kidney Injury ◽  
Acute Interstitial Nephritis ◽  
Mitogen Activated Protein Kinase ◽  
Dermatologic Toxicity ◽  
Mitogen Activated Protein ◽  
Protein Kinase Kinase

A 73-year-old male diagnosed with metastasized malignant melanoma was started on combined therapy with dabrafenib and trametinib, but soon admitted with gastrointestinal intolerance. Blood tests revealed toxic hepatitis and acute kidney injury. Renal duplex Doppler ultrasound ruled out urinary and vascular obstruction and apart from a positive antinuclear antibody, other tests for acute kidney injury assessment were unremarkable. Urinary sediment microscopy showed dysmorphic red blood cells, in addition to yellow-pigmented casts. Kidney biopsy revealed signs of acute tubular necrosis and acute interstitial nephritis. Kidney function declined further, prompting the need for urgent hemodialysis. Treatment with dabrafenib and trametinib was stopped and corticosteroids were initiated, with a rapid beneficial effect on both the kidney function and liver toxicity. Hemodialysis was stopped after four sessions with a full recovery after 2 months of corticosteroids, with the dose being slowly tapered. Unfortunately, the patient died a few months later due to melanoma progression. Dual therapy with the combination of a B-Raf proto-oncogene inhibitor with a mitogen-activated protein kinase kinase inhibitor improves response rates and has been recently approved by the U.S. Food and Drug Administration, and while dermatologic toxicity is a common adverse effect, the association with acute renal failure has seldom been reported. To the best of our knowledge, there are only two published case reports of acute kidney injury in patients treated with combination of dabrafenib and trametinib and only one of them is biopsy proven. Further studies evaluating the incidence of acute kidney injury with the combination of B-Raf proto-oncogene and mitogen-activated protein kinase kinase inhibitors are warranted, and may provide new insights into the mechanisms underlying renal toxicity.

Schisantherin-A Alleviates Lipopolysaccharide-Induced Inflammation and Apoptosis in WI-38 Cells

2021 ◽  
Vol 19 (4) ◽  
pp. 421-426
Author(s):  
Shan Liu ◽  
Banghao Lu
Keyword(s):  
Protein Kinase ◽  
Antioxidant Activities ◽  
Kidney Injury ◽  
Mitogen Activated Protein Kinase ◽  
Protective Effects ◽  
Extracellular Signal ◽  
Acute Pneumonia ◽  
Mitogen Activated Protein ◽  
Anti Inflammatory ◽  
Schisantherin A

Schisantherin A, a dibenzocyclooctadiene lignan, isolated from the fruit of Schisandra sphenanthera has been widely used to exert anti-inflammatory or antioxidant activities in sepsis associated acute kidney injury and lipopolysaccharide associated acute respiratory distress syndrome. However, the protective effects of Schisantherin A against acute pneumonia in lipopolysaccharide-induced WI-38 remain to be explored. To this end, WI-38 cells were treated with lipopolysaccharide to establish an acute pneumonia model and evaluate the effect of Schisantherin A. The data show an increase in apoptosis and decrease in cell viability by lipopolysaccharide treatment that was reversed by Schisantherin A. Also, Schisantherin A dose dependently attenuated lipopolysaccharide-induced increase in proinflammatory cytokines. Lastly, expression of p65, p38 proteins, extracellular-signal-regulated kinase, and Jun N-terminal protein kinase phosphorylation were upregulated by lipopolysaccharide and decreased by Schisantherin A. In conclusion, Schisantherin A demonstrates anti-inflammatory and antiapoptotic roles in lipopolysaccharide induced WI-38 cells through inactivation of nuclear factor-kappa B/mitogen activated protein kinase pathway.

Dual-specificity phosphatases: critical regulators with diverse cellular targets

2009 ◽  
Vol 418 (3) ◽  
pp. 475-489 ◽  
Author(s):  
Kate I. Patterson ◽  
Tilman Brummer ◽  
Philippa M. O'brien ◽  
Roger J. Daly
Keyword(s):  
Protein Kinase ◽  
Sequence Similarity ◽  
Mitogen Activated Protein Kinase ◽  
Cellular Targets ◽  
Dual Specificity ◽  
Extracellular Signal ◽  
Mitogen Activated Protein ◽  
Dual Specificity Phosphatases ◽  
The One ◽  
And Function

DUSPs (dual-specificity phosphatases) are a heterogeneous group of protein phosphatases that can dephosphorylate both phosphotyrosine and phosphoserine/phosphothreonine residues within the one substrate. DUSPs have been implicated as major modulators of critical signalling pathways that are dysregulated in various diseases. DUSPs can be divided into six subgroups on the basis of sequence similarity that include slingshots, PRLs (phosphatases of regenerating liver), Cdc14 phosphatases (Cdc is cell division cycle), PTENs (phosphatase and tensin homologues deleted on chromosome 10), myotubularins, MKPs (mitogen-activated protein kinase phosphatases) and atypical DUSPs. Of these subgroups, a great deal of research has focused on the characterization of the MKPs. As their name suggests, MKPs dephosphorylate MAPK (mitogen-activated protein kinase) proteins ERK (extracellular-signal-regulated kinase), JNK (c-Jun N-terminal kinase) and p38 with specificity distinct from that of individual MKP proteins. Atypical DUSPs are mostly of low-molecular-mass and lack the N-terminal CH2 (Cdc25 homology 2) domain common to MKPs. The discovery of most atypical DUSPs has occurred in the last 6 years, which has initiated a large amount of interest in their role and regulation. In the past, atypical DUSPs have generally been grouped together with the MKPs and characterized for their role in MAPK signalling cascades. Indeed, some have been shown to dephosphorylate MAPKs. The current literature hints at the potential of the atypical DUSPs as important signalling regulators, but is crowded with conflicting reports. The present review provides an overview of the DUSP family before focusing on atypical DUSPs, emerging as a group of proteins with vastly diverse substrate specificity and function.

Albumin stimulates p44/p42 extracellular-signal-regulated mitogen-activated protein kinase in opossum kidney proximal tubular cells

2000 ◽  
Vol 98 (3) ◽  
pp. 295-301 ◽  
Author(s):  
Richard DIXON ◽  
Nigel J. BRUNSKILL
Keyword(s):  
Human Albumin ◽  
Mitogen Activated Protein Kinase ◽  
Proximal Tubular Cells ◽  
Opossum Kidney ◽  
Tubular Cells ◽  
Extracellular Signal ◽  
Mitogen Activated Protein ◽  
Proximal Tubular ◽  
Dose Dependent ◽  
Recombinant Human Albumin

The presence of protein in the urine of patients with renal disease is an adverse prognostic feature. It has therefore been suggested that proteinuria per se may be responsible for the development of renal tubulo-interstitial scarring and fibrosis, and disturbances in tubular cell growth and proliferation. We have used the opossum kidney proximal tubular cell line to investigate the effects of albumin on cell growth. The effect of albumin on cell proliferation was investigated by cell counting and measurement of [3H]thymidine incorporation. We studied the effect of recombinant human albumin on the activity of p44/p42 extracellular-signal-regulated mitogen-activated protein kinase (MAP kinase) using an in vitro kinase assay, and immunoblotting with antibodies against active extracellular-signal-regulated kinase (ERK). The effects of the ERK inhibitor PD98059 were also examined. Recombinant human albumin was found to stimulate proliferation of opossum kidney cells in a dose-dependent manner, with maximal stimulation at a concentration of 1 mg/ml. In addition, recombinant human albumin activated ERK in a time-dependent (maximal after 5 min) and dose-dependent (maximal at 1 mg/ml) fashion. These effects on cell proliferation and ERK activity were inhibited by PD98059, and were not reproduced by ovalbumin or mannitol. The data therefore indicate that albumin is able to stimulate growth and proliferation of proximal tubular cells that is dependent on the ERK family of MAP kinases. The potential importance of this pathway in the development of renal disease is discussed.

scholarly journals Lactoferrin Contributes a Renoprotective Effect in Acute Kidney Injury and Early Renal Fibrosis

Pharmaceutics ◽  
2020 ◽  
Vol 12 (5) ◽  
pp. 434 ◽  
Author(s):  
Yung-Ho Hsu ◽  
I-Jen Chiu ◽  
Yuh-Feng Lin ◽  
Yi-Jie Chen ◽  
Yu-Hsuan Lee ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Renal Fibrosis ◽  
Kidney Injury ◽  
Human Kidney ◽  
Degradation Pathway ◽  
Acute Stage ◽  
Mrna Levels ◽  
Tubular Cells ◽  
Proximal Tubular ◽  
Kidney Proximal Tubular Cells

Patients with acute kidney injury (AKI) who survive the acute stage are at notable risk for chronic kidney disease (CKD) progression. There is no single therapy that can effectively prevent the AKI to CKD transition. Autophagy is a cytoplasmic component degradation pathway and has complex functions in several diseases, such as renal fibrosis. Previous research has shown that lactoferrin has important functions in antioxidant defense and other defense systems, protecting kidneys against various injuries. The present study investigated the effect of lactoferrin in protecting against the AKI to CKD transition. We identified 62 consensus genes with two-fold changes in clinical kidney tissues from AKI and CKD patients. Among the 62 overlay genes, the mRNA levels of LTF were significantly upregulated in the kidney tissues of AKI and CKD patients. Lactoferrin induced autophagy via the activation of the AMPK and inhibition of Akt/mTOR pathway in human kidney proximal tubular cells. Lactoferrin suppressed oxidative stress-induced cell death and apoptosis by augmenting autophagy. Lactoferrin has an antifibrotic role in human kidney tubular cells. In a mouse model of folic acid-induced AKI to CKD transition, treatment with lactoferrin recovered renal function and further suppressed renal fibrosis through the inhibition of apoptosis and the induction of autophagy. These findings identify lactoferrin as a potential therapeutic target for the prevention of the AKI to CKD transition.

Sign in / Sign up

Export Citation Format

Share Document