scholarly journals FGF/FGFR2 Protects against Tubular Cell Death and Acute Kidney Injury Involving Erk1/2 Signaling Activation

2020 ◽  
Vol 6 (3) ◽  
pp. 181-194
Author(s):  
Zhuo Xu ◽  
Xingwen Zhu ◽  
Mingjie Wang ◽  
Yibing Lu ◽  
Chunsun Dai
Keyword(s):  
Acute Kidney Injury ◽  
Cell Death ◽  
Kidney Injury ◽  
Tubular Cell ◽  
Signaling Activation

scholarly journals p53-cyclophilin D mediates renal tubular cell apoptosis in ischemia-reperfusion-induced acute kidney injury

2019 ◽  
Vol 317 (5) ◽  
pp. F1311-F1317 ◽  
Author(s):  
Huan Yang ◽  
Ruizhao Li ◽  
Li Zhang ◽  
Shu Zhang ◽  
Wei Dong ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Cell Death ◽  
Cell Apoptosis ◽  
Ischemia Reperfusion ◽  
Kidney Injury ◽  
Tubular Cell ◽  
Renal Tubular Cell ◽  
Cyclophilin D ◽  
Mptp Opening ◽  
Renal Tubular

Ischemia-reperfusion (I/R)-induced acute kidney injury (I/R-AKI) favors mitochondrial permeability transition pore (mPTP) opening and subsequent cell death. Cyclophilin D (CypD) is an essential component of the mPTP, and recent findings have implicated the p53-CypD complex in cell death. To evaluate the role of p53-CypD after I/R-AKI, we tested the hypothesis that the p53-CypD complex mediates renal tubular cell apoptosis in I/R-AKI via mPTP opening. Expression of p53 and cleaved caspase-3 was significantly increased in rats subjected to I/R-AKI compared with normal controls and sham-operated controls. The underlying mechanisms were determined using an in vitro model of ATP depletion. Inhibition of mPTP opening using the CypD inhibitor cyclosporin A or siRNA for p53 in ATP-depleted HK-2 cells prevented mitochondrial membrane depolarization and reduced apoptosis. Furthermore, p53 bound to CypD in ATP-depleted HK-2 cells. These results suggest that the p53-CypD complex mediates renal tubular cell apoptosis in I/R-AKI via mPTP opening.

scholarly journals Acute Kidney Injury is Aggravated in Aged Mice by the Exacerbation of Proinflammatory Processes

2021 ◽  
Vol 12 ◽  
Author(s):  
Laura Marquez-Exposito ◽  
Lucia Tejedor-Santamaria ◽  
Laura Santos-Sanchez ◽  
Floris A. Valentijn ◽  
Elena Cantero-Navarro ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Cell Death ◽  
Cellular Senescence ◽  
Immune Cells ◽  
Kidney Injury ◽  
Tubular Cell ◽  
Nuclear Staining ◽  
Age Related ◽  
Regulated Necrosis ◽  
Old Mice

Acute kidney injury (AKI) is more frequent in elderly patients. Mechanisms contributing to AKI (tubular cell death, inflammatory cell infiltration, impaired mitochondrial function, and prolonged cell-cycle arrest) have been linked to cellular senescence, a process implicated in regeneration failure and progression to fibrosis. However, the molecular and pathological basis of the age-related increase in AKI incidence is not completely understood. To explore these mechanisms, experimental AKI was induced by folic acid (FA) administration in young (3-months-old) and old (1-year-old) mice, and kidneys were evaluated in the early phase of AKI, at 48 h. Tubular damage score, KIM-1 expression, the recruitment of infiltrating immune cells (mainly neutrophils and macrophages) and proinflammatory gene expression were higher in AKI kidneys of old than of young mice. Tubular cell death in FA-AKI involves several pathways, such as regulated necrosis and apoptosis. Ferroptosis and necroptosis cell-death pathways were upregulated in old AKI kidneys. In contrast, caspase-3 activation was only found in young but not in old mice. Moreover, the antiapoptotic factor BCL-xL was significantly overexpressed in old, injured kidneys, suggesting an age-related apoptosis suppression. AKI kidneys displayed evidence of cellular senescence, such as increased levels of cyclin dependent kinase inhibitors p16ink4a and p21cip1, and of the DNA damage response marker γH2AX. Furthermore, p21cip1 mRNA expression and nuclear staining for p21cip1 and γH2AX were higher in old than in young FA-AKI mice, as well as the expression of senescence-associated secretory phenotype (SASP) components (Il-6, Tgfb1, Ctgf, and Serpine1). Interestingly, some infiltrating immune cells were p21 or γH2AX positive, suggesting that molecular senescence in the immune cells (“immunosenescence”) are involved in the increased severity of AKI in old mice. In contrast, expression of renal protective factors was dramatically downregulated in old AKI mice, including the antiaging factor Klotho and the mitochondrial biogenesis driver PGC-1α. In conclusion, aging resulted in more severe AKI after the exposure to toxic compounds. This increased toxicity may be related to magnification of proinflammatory-related pathways in older mice, including a switch to a proinflammatory cell death (necroptosis) instead of apoptosis, and overactivation of cellular senescence of resident renal cells and infiltrating inflammatory cells.

scholarly journals Rictor/mTORC2 protects against cisplatin-induced tubular cell death and acute kidney injury

2014 ◽  
Vol 86 (1) ◽  
pp. 86-102 ◽  
Author(s):  
Jianzhong Li ◽  
Zhuo Xu ◽  
Lei Jiang ◽  
Junhua Mao ◽  
Zhifeng Zeng ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Cell Death ◽  
Kidney Injury ◽  
Tubular Cell

scholarly journals Fibroblast mTOR/PPARγ/HGF axis protects against tubular cell death and acute kidney injury

2019 ◽  
Vol 26 (12) ◽  
pp. 2774-2789 ◽  
Author(s):  
Yuan Gui ◽  
Qingmiao Lu ◽  
Mengru Gu ◽  
Mingjie Wang ◽  
Yan Liang ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Cell Death ◽  
Kidney Injury ◽  
Tubular Cell

scholarly journals Protective Effects of 6-Shogaol, an Active Compound of Ginger, in a Murine Model of Cisplatin-Induced Acute Kidney Injury

Molecules ◽  
2021 ◽  
Vol 26 (19) ◽  
pp. 5931
Author(s):  
Mi-Gyeong Gwon ◽  
Hyemin Gu ◽  
Jaechan Leem ◽  
Kwan-Kyu Park
Keyword(s):  
Oxidative Stress ◽  
Acute Kidney Injury ◽  
Cell Death ◽  
Side Effect ◽  
Immune Cell ◽  
Inflammatory Diseases ◽  
Kidney Injury ◽  
Tubular Cell ◽  
Therapeutic Effects ◽  
Protective Effects

Acute kidney injury (AKI) is a dose-limiting side effect of cisplatin therapy in cancer patients. However, effective therapies for cisplatin-induced AKI are not available. Oxidative stress, tubular cell death, and inflammation are known to be the major pathological processes of the disease. 6-Shogaol is a major component of ginger and exhibits anti-oxidative and anti-inflammatory effects. Accumulating evidence suggest that 6-shogaol may serve as a potential therapeutic agent for various inflammatory diseases. However, whether 6-shogaol exerts a protective effect on cisplatin-induced renal side effect has not yet been determined. The aim of this study was to evaluate the effect of 6-shogaol on cisplatin-induced AKI and to investigate its underlying mechanisms. An administration of 6-shogaol after cisplatin treatment ameliorated renal dysfunction and tubular injury, as shown by a reduction in serum levels of creatinine and blood urea nitrogen and an improvement in histological abnormalities. Mechanistically, 6-shogaol attenuated cisplatin-induced oxidative stress and modulated the renal expression of prooxidant and antioxidant enzymes. Apoptosis and necroptosis induced by cisplatin were also suppressed by 6-shogaol. Moreover, 6-shogaol inhibited cisplatin-induced cytokine production and immune cell infiltration. These results suggest that 6-shogaol exhibits therapeutic effects against cisplatin-induced AKI via the suppression of oxidative stress, tubular cell death, and inflammation.

scholarly journals Cyclophilin Inhibition Protects Against Experimental Acute Kidney Injury and Renal Interstitial Fibrosis

2020 ◽  
Vol 22 (1) ◽  
pp. 271
Author(s):  
Khai Gene Leong ◽  
Elyce Ozols ◽  
John Kanellis ◽  
Shawn S. Badal ◽  
John T. Liles ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Cell Death ◽  
Renal Fibrosis ◽  
Ischemia Reperfusion Injury ◽  
Therapeutic Potential ◽  
Tissue Injury ◽  
Interstitial Fibrosis ◽  
Ischemia Reperfusion ◽  
Kidney Injury ◽  
Tubular Cell

Cyclophilins have important homeostatic roles, but following tissue injury, cyclophilin A (CypA) can promote leukocyte recruitment and inflammation, while CypD can facilitate mitochondrial-dependent cell death. This study investigated the therapeutic potential of a selective cyclophilin inhibitor (GS-642362), which does not block calcineurin function, in mouse models of tubular cell necrosis and renal fibrosis. Mice underwent bilateral renal ischemia/reperfusion injury (IRI) and were killed 24 h later: treatment with 10 or 30 mg/kg/BID GS-642362 (or vehicle) began 1 h before surgery. In the second model, mice underwent unilateral ureteric obstruction (UUO) surgery and were killed 7 days later; treatment with 10 or 30 mg/kg/BID GS-642362 (or vehicle) began 1 h before surgery. GS-642362 treatment gave a profound and dose-dependent protection from acute renal failure in the IRI model. This protection was associated with reduced tubular cell death, including a dramatic reduction in neutrophil infiltration. In the UUO model, GS-642362 treatment significantly reduced tubular cell death, macrophage infiltration, and renal fibrosis. This protective effect was independent of the upregulation of IL-2 and activation of the stress-activated protein kinases (p38 and JNK). In conclusion, GS-642362 was effective in suppressing both acute kidney injury and renal fibrosis. These findings support further investigation of cyclophilin blockade in other types of acute and chronic kidney disease.

Pathogenesis of Acute Kidney Injury

2019 ◽  
pp. 11-20
Author(s):  
David P. Basile ◽  
Babu J. Padanilam
Keyword(s):  
Acute Kidney Injury ◽  
Cell Death ◽  
Renal Function ◽  
Fatty Acid ◽  
Interstitial Fibrosis ◽  
Kidney Injury ◽  
Acid Oxidation ◽  
Clinical Disorder ◽  
Successful Recovery ◽  
Multiple Issues

Acute kidney injury represents a significant clinical disorder associated with a rapid loss of renal function following a variety of potential insults. This chapter reviews multiple issues related to the pathophysiology of AKI with an emphasis on studies from animal models. Early responses following kidney injury include impaired hemodynamic and bioenergetic responses. Reductions in renal ATP levels occur as a result of compromised fatty acid oxidation and impaired compensation by glycolysis. Sustained reductions in perfusion contribute to extension of AKI characterized by complex inflammatory and cellular injury responses, often leading to cell death. Concurrently, the kidney displays an elegant repair response, leading to successful recovery in most cases, characterized in part by epithelial cell growth, while maladaptive or incomplete recovery of tubules or capillaries can predispose the development of interstitial fibrosis and CKD progression.

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