scholarly journals Ferroptotic stress promotes the accumulation of pro-inflammatory proximal tubular cells in maladaptive renal repair

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Shintaro Ide ◽  
Yoshihiko Kobayashi ◽  
Kana Ide ◽  
Sarah A Strausser ◽  
Koki Abe ◽  
...  
Keyword(s):  
Cell Death ◽  
Glutathione Metabolism ◽  
Proximal Tubular Cells ◽  
Tubular Cells ◽  
Renal Repair ◽  
Regulated Cell Death ◽  
Persistent Inflammation ◽  
Inflammatory State ◽  
Proximal Tubular ◽  
Mouse Genetic

Overwhelming lipid peroxidation induces ferroptotic stress and ferroptosis, a non-apoptotic form of regulated cell death that has been implicated in maladaptive renal repair in mice and humans. Using single-cell transcriptomic and mouse genetic approaches, we show that proximal tubular (PT) cells develop a molecularly distinct, pro-inflammatory state following injury. While these inflammatory PT cells transiently appear after mild injury and return to their original state without inducing fibrosis, after severe injury they accumulate and contribute to persistent inflammation. This transient inflammatory PT state significantly downregulates glutathione metabolism genes, making the cells vulnerable to ferroptotic stress. Genetic induction of high ferroptotic stress in these cells after mild injury leads to the accumulation of the inflammatory PT cells, enhancing inflammation and fibrosis. Our study broadens the roles of ferroptotic stress from being a trigger of regulated cell death to include the promotion and accumulation of proinflammatory cells that underlie maladaptive repair.

scholarly journals Ferroptotic stress promotes the accumulation of pro-inflammatory proximal tubular cells in maladaptive renal repair

2021 ◽  
Author(s):  
Shintaro Ide ◽  
Yoshihiko Kobayashi ◽  
Kana Ide ◽  
Sarah A Strausser ◽  
Savannah Herbek ◽  
...  
Keyword(s):  
Cell Death ◽  
Glutathione Metabolism ◽  
Proximal Tubular Cells ◽  
Tubular Cells ◽  
Renal Repair ◽  
Regulated Cell Death ◽  
Persistent Inflammation ◽  
Inflammatory State ◽  
Proximal Tubular ◽  
Mouse Genetic

Overwhelming lipid peroxidation induces ferroptotic stress and ferroptosis, a non-apoptotic form of regulated cell death that has been implicated in maladaptive renal repair in mice and humans. Using single-cell transcriptomic and mouse genetic approaches, we show that proximal tubular (PT) cells develop a molecularly distinct, pro inflammatory state following injury. While these inflammatory PT cells transiently appear after mild injury and return to their original state without inducing fibrosis, they accumulate and contribute to persistent inflammation after severe injury. This transient inflammatory PT state significantly downregulates glutathione metabolism genes, making them vulnerable to ferroptotic stress. Genetic induction of high ferroptotic stress in these cells after mild injury leads to the accumulation of the inflammatory PT cells, enhancing inflammation and fibrosis. Our study broadens the roles of ferroptotic stress from being a trigger of regulated cell death to include the promotion and accumulation of proinflammatory cells that underlie maladaptive repair.

scholarly journals Palmitate aggravates proteinuria-induced cell death and inflammation via CD36-inflammasome axis in the proximal tubular cells of obese mice

2018 ◽  
Vol 315 (6) ◽  
pp. F1720-F1731 ◽  
Author(s):  
Lung-Chih Li ◽  
Jenq-Lin Yang ◽  
Wen-Chin Lee ◽  
Jin-Bor Chen ◽  
Chien-Te Lee ◽  
...  
Keyword(s):  
Cell Death ◽  
Tubular Injury ◽  
Proximal Tubular Cells ◽  
Tubular Cells ◽  
Renal Tubular Cells ◽  
Caspase 1 ◽  
Proximal Tubular ◽  
Renal Tubular ◽  
Nlrp3 Inflammasomes

High levels of serum free fatty acids (FFAs) and proteinuria have been implicated in the pathogenesis of obesity-related nephropathy. CD36, a class B scavenger receptor, is highly expressed in the renal proximal tubules and mediates FFA uptake. It is not clear whether FFA- and proteinuria-mediated CD36 activation coordinates NLRP3 inflammasomes to induce renal tubular injury and inflammation. In this study, we investigated the roles of CD36 and NLRP3 inflammasomes in FFA-induced renal injury in high-fat diet (HFD)-induced obesity. HFD-fed C57BL/6 mice and palmitate-treated HK2 renal tubular cells were used as in vivo and in vitro models. Immunohistochemical staining showed that CD36, IL-1β, and IL-18 levels increased progressively in the kidneys of HFD-fed mice. Sulfo- N-succinimidyl oleate (SSO), a CD36 inhibitor, attenuated the HFD-induced upregulation of NLRP3, IL-1β, and IL-18 and suppressed the colocalization of NLRP3 and ASC in renal tubular cells. In vitro, SSO abolished the palmitate-induced activation of IL-1β, IL-18, and caspase-1 in HK2 proximal tubular cells. Furthermore, treatment with SSO and the knockdown of caspase-1 expression by siRNA both inhibited palmitate-induced cell death and apoptosis in HK2 cells. Collectively, palmitate causes renal tubular inflammation, cell death, and apoptosis via the CD36/NLRP3/caspase-1 axis, which may explain, at least in part, the mechanism underlying FFA-related renal tubular injury. The blockade of CD36-induced cellular processes is therefore a promising strategy for treating obesity-related nephropathy.

scholarly journals Renal proximal tubular cells acquire resistance to cell death stimuli in mice with hereditary tyrosinemia type 1

2004 ◽  
Vol 66 (3) ◽  
pp. 990-1000 ◽  
Author(s):  
Marjanka C. Luijerink ◽  
Ellen A.C.M. Van Beurden ◽  
Helga E.M. Malingré ◽  
Saskia M.M. Jacobs ◽  
Markus Grompe ◽  
...  
Keyword(s):  
Cell Death ◽  
Proximal Tubular Cells ◽  
Tubular Cells ◽  
Proximal Tubular ◽  
Tyrosinemia Type 1 ◽  
Renal Proximal Tubular Cells ◽  
Renal Proximal Tubular ◽  
Hereditary Tyrosinemia

p-Cresol mediates autophagic cell death in renal proximal tubular cells

2015 ◽  
Vol 234 (1) ◽  
pp. 20-29 ◽  
Author(s):  
Hsin-Hung Lin ◽  
Chiu-Ching Huang ◽  
Tze-Yi Lin ◽  
Ching-Yuang Lin
Keyword(s):  
Cell Death ◽  
Autophagic Cell Death ◽  
Proximal Tubular Cells ◽  
Tubular Cells ◽  
Proximal Tubular ◽  
Renal Proximal Tubular Cells ◽  
Renal Proximal Tubular

Pathways of glutathione metabolism and transport in isolated proximal tubular cells from rat kidney

1996 ◽  
Vol 52 (2) ◽  
pp. 259-272 ◽  
Author(s):  
Theresa M. Visarius ◽  
David A. Putt ◽  
Joshua M. Schare ◽  
David M. Pegouske ◽  
Lawrence H. Lash
Keyword(s):  
Rat Kidney ◽  
Glutathione Metabolism ◽  
Proximal Tubular Cells ◽  
Tubular Cells ◽  
Proximal Tubular

In vivo and in vitro detachment of proximal tubular cells and F-actin damage: consequences for renal function

1994 ◽  
Vol 267 (5) ◽  
pp. F888-F899 ◽  
Author(s):  
B. Van de Water ◽  
J. J. Jaspers ◽  
D. H. Maasdam ◽  
G. J. Mulder ◽  
J. F. Nagelkerke
Keyword(s):  
Cell Death ◽  
Focal Adhesions ◽  
Free Calcium ◽  
Cell Detachment ◽  
Proximal Tubular Cells ◽  
Acetoxymethyl Ester ◽  
Tubular Cells ◽  
Proximal Tubular

We investigated the relationship between F-actin damage and cell detachment using nephrotoxic L-cysteine S-conjugates. In vivo S-(1,2-dichlorovinyl)-L-cysteine (DCVC) induced loss of F-actin in the S3 segment of the proximal tubule in the outer stripe of the outer medulla, which was associated with loss of the brush border and loss of cells from the basement membrane. In vitro DCVC caused the detachment of primary cultured rat renal proximal tubular cells (PTC), which was clearly associated with F-actin damage. Disorganization of F-actin correlated with an increase in cellular levels of G-actin, indicating depolymerization of F-actin. Cell detachment was preceded by a complete loss of the alpha-actinin binding protein talin from the focal adhesions, which was directly associated with F-actin disorganization. Inhibition of formation of highly reactive metabolites from L-cysteine S-conjugates by L-cysteine-S-conjugate beta-lyase completely prevented both F-actin damage and cell detachment by DCVC. Although inhibition of DCVC-induced lipid peroxidation and reduction of intracellular free calcium by N,N'-diphenyl-p-phenylenediamine and the acetoxymethyl ester of ethylene glycol-bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid, respectively, clearly prevented cell death, no protection was observed against the DCVC-induced F-actin disorganization, talin redistribution, and cell detachment. Also, F-actin damage was unrelated to changes in the energy status of the PTC, since cellular ATP content was unaffected. The data clearly demonstrate a close relationship between F-actin damage, disturbances of focal adhesions, and cell detachment. In addition, different molecular pathways are involved in the cell detachment caused by F-actin disorganization and initiation of cell death.

The Use of Porcine Proximal Tubular Cells for Studying Nephrotoxicity In Vitro: The Role of Oxidative Stress in Cisplatin-induced Cell Death

1996 ◽  
Vol 24 (2) ◽  
pp. 161-172 ◽  
Author(s):  
Marieke Kruidering ◽  
Bob van de Water ◽  
Emile de Heer ◽  
Gerard J. Mulder ◽  
J. Fred Nagelkerke
Keyword(s):  
Cell Death ◽  
Complex I ◽  
Proximal Tubular Cells ◽  
Complex Ii ◽  
Tubular Cells ◽  
Dependent Inhibition ◽  
Proximal Tubular ◽  
Ros Formation ◽  
Dose Dependent Inhibition

The effects of a widely used antitumour drug, cisplatin, on freshly isolated porcine proximal tubular cells (PPTC) in suspension were investigated. Incubation of the PPTC with 5-500μM cisplatin resulted in a decrease in mitochondrial membrane potential (MMP) and in cell death. In addition, the formation of reactive oxygen species (ROS) was observed within 20 minutes. Prevention of ROS formation with the antioxidants diphenyl- p-phenylene-diamine (DPPD) or desferrioxamine had no effect on the cisplatin-induced effects on MMP and cell death, implying that cisplatin-induced ROS formation is not a cause of cell death. In order to investigate whether the ROS formation was related to mitochondrial damage, we determined the effects of cisplatin on the enzymatic activities of NADP:ubiquinone reductase (Complex I) and succinate:ubiquinone reductase (Complex II) of the respiratory chain. Exposure of the PPTC to cisplatin resulted in a time-dependent and dose-dependent inhibition of the activities of both Complex I and Complex II. The inhibition of these activities and the depletion of ATP could not be prevented by the antioxidants, indicating that these effects are not a consequence of ROS formation. We propose that damage to the mitochondria could be a key event in cisplatin-induced cell death.

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