Farrerol Ameliorated Cisplatin-Induced Chronic Kidney Disease Through Mitophagy Induction via Nrf2/PINK1 Pathway

Previously, Our study has showed that farrerol can activate Nrf2 and ameliorate cisplatin-induced acute kidney injury (AKI). Mitophagy reportedly can prevent diabetic nephropathy, cisplatin-induced AKI and other related nephropathy. In this study, we evaluated the correlation between mitophagy and the protective effect of the Nrf2 activator farrerol on cisplatin-induced CKD by using C57BL/6 wild-type and Nrf2 knockout mice. We confirmed that Nrf2 and PINK1/Parkin-mediated mitophagy was significantly increased on the 3rd day of cisplatin stimulation but was reduced on the 38th day of cisplatin stimulation. Similar to previous results, farrerol activated Nrf2 on the 38th day of cisplatin administration, subsequently stimulating the Nrf2-targeted antioxidant enzymes HO-1 and NQO1. In addition, farrerol triggered PINK1/Parkin-mediated mitophagy by recruiting the receptor proteins LC3 and p62/SQSTM1, thereby eliminating damaged mitochondria. Furthermore, genetic deletion of Nrf2 reduced PINK1/Parkin-mediated mitophagy activation and led to increased renal tubular necrosis and renal fibrosis. We also found that farrerol alleviated inflammation and renal fibrosis by inhibiting p-NF-κB/NLRP3 and TGF-β/Smad signaling. These data indicated that farrerol effectively inhibited cisplatin-induced inflammation and renal fibrosis by activating Nrf2 and PINK1/Parkin-mediated mitophagy, which provides a potential novel therapeutic target for CKD.

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Peptidyl arginine deiminase-4-deficient mice are protected against kidney and liver injury after renal ischemia and reperfusion

AJP Renal Physiology ◽

10.1152/ajprenal.00254.2016 ◽

2016 ◽

Vol 311 (2) ◽

pp. F437-F449 ◽

Cited By ~ 25

Author(s):

May Rabadi ◽

Mihwa Kim ◽

Vivette D'Agati ◽

H. Thomas Lee

Keyword(s):

Inflammatory Response ◽

Nuclear Translocation ◽

Neutrophil Infiltration ◽

Arginine Deiminase ◽

Ischemia And Reperfusion ◽

Wild Type ◽

Tubular Necrosis ◽

Renal Tubular ◽

Deficient Mice ◽

Renal Tubular Necrosis

We previously demonstrated that renal peptidyl arginine deiminase-4 (PAD4) is induced after renal ischemia and reperfusion (I/R) injury and exacerbates acute kidney injury (AKI) by increasing the renal tubular inflammatory response. Here, we tested whether genetic ablation of PAD4 attenuates renal injury and inflammation after I/R in mice. After renal I/R, PAD4 wild-type mice develop severe AKI with large increases in plasma creatinine, neutrophil infiltration, as well as significant renal tubular necrosis, apoptosis, and proinflammatory cytokine generation. In contrast, PAD4-deficient mice are protected against ischemic AKI with reduced real tubular neutrophil infiltration, renal tubular necrosis, and apoptosis. In addition, hepatic injury and inflammation observed in PAD4 wild-type mice after renal I/R are significantly attenuated in PAD4-deficient mice. We also show that increased renal tubular PAD4 expression after renal I/R is associated with translocation of PAD4 from the nucleus to the cytosol. Consistent with PAD4 cytosolic translocation, we show increased renal tubular cytosolic peptidyl-citrullination after ischemic AKI. Mechanistically, recombinant PAD4 treatment increased nuclear translocation of NF-κB in cultured human as well as murine proximal tubule cells that is inhibited by a PAD4 inhibitor (2-chloroamidine). Taken together, our studies further support the hypothesis that renal tubular PAD4 plays a critical role in renal I/R injury by increasing the renal tubular inflammatory response and neutrophil infiltration after renal I/R perhaps by interacting with the proinflammatory transcription factor NF-κB in the cytosol and promoting its nuclear translocation.

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Erythema multiforme associated with acute renal tubular necrosis

Archives of Dermatology ◽

10.1001/archderm.92.4.367 ◽

1965 ◽

Vol 92 (4) ◽

pp. 367-372 ◽

Cited By ~ 3

Author(s):

S. M. Bluefarb

Keyword(s):

Erythema Multiforme ◽

Tubular Necrosis ◽

Renal Tubular ◽

Renal Tubular Necrosis

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ApoSense: a novel technology for functional molecular imaging of cell death in models of acute renal tubular necrosis

European Journal of Nuclear Medicine and Molecular Imaging ◽

10.1007/s00259-005-1905-x ◽

2005 ◽

Vol 33 (3) ◽

pp. 281-291 ◽

Cited By ~ 59

Author(s):

Maya Damianovich ◽

Ilan Ziv ◽

Samuel N. Heyman ◽

Seymour Rosen ◽

Ahuva Shina ◽

...

Keyword(s):

Cell Death ◽

Molecular Imaging ◽

Tubular Necrosis ◽

Novel Technology ◽

Renal Tubular ◽

Renal Tubular Necrosis

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Renal Tubular Necrosis and Papillary Necrosis after Gastroenteritis in Infants

BMJ ◽

10.1136/bmj.1.5693.410 ◽

1970 ◽

Vol 1 (5693) ◽

pp. 410-412 ◽

Cited By ~ 22

Author(s):

A. R. Chrispin ◽

D. Hull ◽

J. G. Lillie ◽

R. A. Ridson

Keyword(s):

Papillary Necrosis ◽

Tubular Necrosis ◽

Renal Tubular ◽

Renal Tubular Necrosis

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Urinary TCP1-eta: A Cortical Damage Marker for the Pathophysiological Diagnosis and Prognosis of Acute Kidney Injury

Toxicological Sciences ◽

10.1093/toxsci/kfz242 ◽

2019 ◽

Vol 174 (1) ◽

pp. 3-15 ◽

Cited By ~ 3

Author(s):

Sandra M Sancho-Martínez ◽

Fernando Sánchez-Juanes ◽

Víctor Blanco-Gozalo ◽

Miguel Fontecha-Barriuso ◽

Laura Prieto-García ◽

...

Keyword(s):

Acute Kidney Injury ◽

Kidney Injury ◽

Cortical Damage ◽

Renal Tubular Cells ◽

Tubular Necrosis ◽

Diagnosis And Prognosis ◽

A Cell ◽

Renal Tubular ◽

Dextran Solution

Abstract Acute kidney injury (AKI) is a serious syndrome with increasing incidence and health consequences, and high mortality rate among critically ill patients. Acute kidney injury lacks a unified definition, has ambiguous semantic boundaries, and relies on defective diagnosis. This, in part, is due to the absence of biomarkers substratifying AKI patients into pathophysiological categories based on which prognosis can be assigned and clinical treatment differentiated. For instance, AKI involving acute tubular necrosis (ATN) is expected to have a worse prognosis than prerenal, purely hemodynamic AKI. However, no biomarker has been unambiguously associated with tubular cell death or is able to provide etiological distinction. We used a cell-based system to identify TCP1-eta in the culture medium as a noninvasive marker of damaged renal tubular cells. In rat models of AKI, TCP1-eta was increased in the urine co-relating with renal cortical tubule damage. When kidneys from ATN rats were perfused in situ with Krebs-dextran solution, a portion of the urinary TCP1-eta protein content excreted into urine disappeared, and another portion remained within the urine. These results indicated that TCP1-eta was secreted by tubule cells and was not fully reabsorbed by the damaged tubules, both effects contributing to the increased urinary excretion. Urinary TCP1-eta is found in many etiologically heterogeneous AKI patients, and is statistically higher in patients partially recovered from severe AKI. In conclusion, urinary TCP1-eta poses a potential, substratifying biomarker of renal cortical damage associated with bad prognosis.

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Simian Virus 40-Associated Fatal Interstitial Pneumonia and Renal Tubular Necrosis in a Rhesus Monkey

The Journal of Infectious Diseases ◽

10.1093/infdis/142.4.618 ◽

1980 ◽

Vol 142 (4) ◽

pp. 618-622 ◽

Cited By ~ 32

Author(s):

W. D. Sheffield ◽

J. D. Strandberg ◽

L. Braun ◽

K. Shah ◽

S. S. Kalter

Keyword(s):

Rhesus Monkey ◽

Interstitial Pneumonia ◽

Simian Virus 40 ◽

Simian Virus ◽

Tubular Necrosis ◽

Renal Tubular ◽

Renal Tubular Necrosis

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Maternal undernutrition aggravates renal tubular necrosis and interstitial fibrosis after unilateral ureteral obstruction in male rat offspring

PLoS ONE ◽

10.1371/journal.pone.0221686 ◽

2019 ◽

Vol 14 (9) ◽

pp. e0221686

Author(s):

Midori Awazu ◽

Tokiya Abe ◽

Akinori Hashiguchi ◽

Mariko Hida

Keyword(s):

Ureteral Obstruction ◽

Interstitial Fibrosis ◽

Unilateral Ureteral Obstruction ◽

Male Rat ◽

Maternal Undernutrition ◽

Rat Offspring ◽

Tubular Necrosis ◽

Renal Tubular ◽

Renal Tubular Necrosis

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Glucose-regulated protein 75 in foodborne disease models induces renal tubular necrosis

Food and Chemical Toxicology ◽

10.1016/j.fct.2019.110720 ◽

2019 ◽

Vol 133 ◽

pp. 110720 ◽

Cited By ~ 3

Author(s):

Xuan Yang ◽

Yijia Li ◽

Lirong Zheng ◽

Xiaoyun He ◽

Yunbo Luo ◽

...

Keyword(s):

Disease Models ◽

Foodborne Disease ◽

Tubular Necrosis ◽

Renal Tubular ◽

Glucose Regulated Protein ◽

Renal Tubular Necrosis

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P0518VNN1 MEDIATES RENAL MALADAPTIVE REPAIR AFTER AKI BY INDUCING PREMATURE SENESCENCE OF RENAL TUBUAR CELLS

Nephrology Dialysis Transplantation ◽

10.1093/ndt/gfaa142.p0518 ◽

2020 ◽

Vol 35 (Supplement_3) ◽

Author(s):

Yani He ◽

Kehong Chen ◽

Jia Chen

Keyword(s):

Renal Fibrosis ◽

Sham Group ◽

Renal Tissue ◽

Premature Senescence ◽

Wild Type ◽

Injury Score ◽

Tubular Cells ◽

Renal Tubular Cells ◽

Tubule Cells ◽

Renal Tubular

Abstract Background and Aims Renal maladaptive repair after acute kidney injury (AKI) can easily progress to chronic kidney disease. Sustained renal interstitial damage caused by accelerated senescence of renal tubular cells leads to renal fibrosis. Vanin-1 (VNN1) is an extracellular enzyme with panthenylmethylaminease activity that indirectly reduces the synthesis of glutathione, causing oxidative stress. The purpose of this study was to investigate the expression and of VNN1 in renal tissue and to study its role in senescence of renal tubular cells after ischemia reperfusion (I/R). Method hirty male wild BALB/c mice were randomly divided into control group, sham group and I/R group. In the I/R group, the bilateral renal pedicle was ligatured for 35 min followed by reperfusion. The expression of VNN1 and aging markers (P16, P21, SA-b-gal) were detected. Furthermore, wild type mice and VNN1 knockout mice were used to compare the degree of renal tissue and functional damage and the senescence of renal tubular cells after I/R injury. Results Compared with sham group, Scr, BUN and renal injury score increased significantly in I/R group at the early stage (3d) of renal injury. Renal fibrosis was observed in the later stage (28-42d). The expression of VNN1 in renal tubular cells of I/R group increased after I/R injury. VNN1 was coexpressed with P16, suggesting that VNN1 might be related to cellular stress senescence. The SCr, BUN of VNN1 KO mice was significantly lower than that of wild type mice at 7-28 d after renal reperfusion. The renal interstitial injury score of VNN1 KO mice was significantly lower than that of wild type mice, and the renal interstitial fibrosis level was significantly higher than that of wild type mice at 42d after reperfusion. The results suggest that VNN1 KO promotes renal repair of AKI. The ratio of P16 positive tubule cells in VNN1 KO mice was significantly higher than that in wild-type mice at 7d after renal reperfusion, suggesting that VNN1 could promote the senescence of renal tubule cells during AKI repair. Conclusion VNN1 mediates renal maladaptive repair after AKI by inducing premature senescence of renal tubular cells.

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