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.

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.

scholarly journals Necrostatin-1 accelerates time to death in a rat model of cecal ligation and puncture and massively increases hepatocyte caspase-3 cleavage

2019 ◽  
Vol 316 (4) ◽  
pp. G551-G561 ◽  
Author(s):  
Qin Zhang ◽  
Siwei Wei ◽  
Jiayin Lu ◽  
Weijun Fu ◽  
Hui Chen ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Liver Injury ◽  
Survival Time ◽  
Caspase 3 ◽  
Cecal Ligation ◽  
B Cell Lymphoma ◽  
Cecal Ligation And Puncture ◽  
Interacting Protein ◽  
Regulated Necrosis ◽  
Related Proteins

Necroptosis, a form of regulated necrosis, has been reported to be involved in numerous pathologies, including sepsis. However, a protective effect of the selective inhibitor of necroptosis, necrostatin-1 (Nec-1), against sepsis remains to be confirmed. Animals (rats and mice) were subjected to cecal ligation and puncture (CLP) to mimic clinical sepsis. Nec-1 or its vehicle (control) was administered 20 min before CLP. Survival time was observed up to 72 h after CLP. Specimens of liver tissue and serum were obtained at 6 h, 12 h, and 18 h. Expression of necroptosis-related proteins [receptor-interacting protein kinase (RIP)1, RIP3, and mixed lineage kinase domain-like (MLKL)] was determined by Western blot analysis. The RIP1/RIP3 interaction and the recruitment of MLKL to RIP3 were also analyzed. Liver function, histopathological changes, serum inflammation cytokines, TUNEL staining, and the expression of apoptosis-related protein, including caspase-3, B-cell lymphoma 2 (Bcl-2), and Bcl-2-associated X (Bax), was determined. As expected, Nec-1 administration reduced the expression of necroptosis-related proteins and the RIP1/RIP3 interaction, indicating inhibited necroptosis. Surprisingly, Nec-1 treatment exacerbated the liver injury and shortened survival time of septic rats with increased TUNEL-positive cells, cleaved caspase-3 protein content, and Bax/Bcl-2 ratio. Collectively, these findings show that Nec-1 administration inhibited the hepatocyte necroptosis pathway but accelerated apoptosis via the apoptotic pathway in CLP-induced sepsis rat. NEW & NOTEWORTHY The present study demonstrated that a chemical inhibitor necrostatin-1 (Nec-1) or receptor-interacting protein kinase(RIP1) knock down targeted at necroptosis inhibition accelerated liver injury of following sepsis. For fundamental research, these results warrant further investigation of the potential link between Nec-1 administration and the cellular apoptosis following sepsis induced liver injury. For applied research, these results suggest the potential harmful effect of Nec-1 on future sepsis treatment.

scholarly journals Sepsis-induced acute kidney injury: kidney protection effects by antioxidants

2018 ◽  
Vol 71 (4) ◽  
pp. 1921-1927 ◽  
Author(s):  
Carolina Ferreira Vasco ◽  
Mirian Watanabe ◽  
Cassiane Dezoti da Fonseca ◽  
Maria de Fátima Fernandes Vattimo
Keyword(s):  
Blood Pressure ◽  
Acute Kidney Injury ◽  
Creatinine Clearance ◽  
Experimental Model ◽  
Kidney Function ◽  
Cecal Ligation ◽  
Kidney Injury ◽  
Cecal Ligation And Puncture ◽  
Antioxidant Action ◽  
Average Blood Pressure

ABSTRACT Objective: To evaluate the antioxidant action of N-acetylcysteine and diosmin-hesperidin in an experimental model of sepsis-induced acute kidney injury in rats. Methods: The study used 20 Wistar adult male rats divided into the following groups: control (laparotomy with no induction of abdominal sepsis), sepsis (experimental model of sepsis with cecal ligation and puncture), N-acetylcysteine + sepsis and diosmin-hesperidin + sepsis. The evaluation contemplated physiological parameters (temperature, glycemia, and average blood pressure), kidney function (creatinine clearance), oxidative stress (urinary peroxides) and kidney histology. Results: The animals submitted to cecal ligation and puncture (sepsis) presented lower body temperature, lower average blood pressure, reduced creatinine clearance and increased urinary hydrogen peroxide levels. Treatment with diosmin-hesperidin improved kidney function and led to a reduction in the excretion of oxidative metabolites. Conclusion: The present study highlighted the protective antioxidant action of diosmin-hesperidin in the experimental model of sepsis-induced acute kidney injury.

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.

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