Inhibition of RIP1-RIP3-mediated necroptosis attenuates renal fibrosis via Wnt3α/β-catenin/GSK-3β signaling in unilateral ureteral obstruction

Piao, Shang Guo; Ding, Jian; Lin, Xue Jing; Nan, Qi Yan; Xuan, Mei Ying; Jiang, Yu; Zheng, Hongliang; Jin, Ji Zhe; Li, Can

doi:10.1371/journal.pone.0274116

Cited by 6 publications

(4 citation statements)

References 31 publications

(37 reference statements)

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“…A previous study showed that necroptosis plays a more significant role in mediating tubular cell injury than apoptosis in the subtotal nephrectomy model of CKD [ 81 ]. Moreover, recent studies have shown that inhibition of necroptosis attenuated UUO-induced renal interstitial fibrosis and inflammation [ 82 , 83 ]. In this study, CS treatment remarkably inhibited UUO-induced apoptosis and necroptosis, as evidenced by a decrease in the number of TUNEL-positive cells and the expression of key factors related to apoptosis (cleaved caspase-3, cleaved PARP-1, p53 and Bax) and necroptosis (RIPK1, RIPK3 and MLKL).…”

Section: Discussionmentioning

confidence: 99%

Protective Effects of Carnosol on Renal Interstitial Fibrosis in a Murine Model of Unilateral Ureteral Obstruction

2022

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Renal fibrosis is a common feature of chronic kidney disease and is a promising therapeutic target. However, there is still limited treatment for renal fibrosis, so the development of new anti-fibrotic agents is urgently needed. Accumulating evidence suggest that oxidative stress and endoplasmic reticulum (ER) stress play a critical role in renal fibrosis. Carnosol (CS) is a bioactive diterpene compound present in rosemary plants and has potent antioxidant and anti-inflammatory properties. In this study, we investigated the potential effects of CS on renal injury and fibrosis in a murine model of unilateral ureteral obstruction (UUO). Male C57BL/6J mice underwent sham or UUO surgery and received intraperitoneal injections of CS (50 mg/kg) daily for 8 consecutive days. CS improved renal function and ameliorated renal tubular injury and interstitial fibrosis in UUO mice. It suppressed oxidative injury by inhibiting pro-oxidant enzymes and activating antioxidant enzymes. Activation of ER stress was also attenuated by CS. In addition, CS inhibited apoptotic and necroptotic cell death in kidneys of UUO mice. Furthermore, cytokine production and immune cell infiltration were alleviated by CS. Taken together, these findings indicate that CS can attenuate renal injury and fibrosis in the UUO model.

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Section: Discussionmentioning

confidence: 99%

Protective Effects of Carnosol on Renal Interstitial Fibrosis in a Murine Model of Unilateral Ureteral Obstruction

2022

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“…This suggests that this necrotic induction of NCB0846 in mammary epithelial cells may have occurred through the WntβcateninNFκB axis. Indeed, many studies have proven that Wnt/βcatenin signaling mediates necroptosis [15,16].…”

Section: Discussionmentioning

confidence: 99%

Determination Of Selective Cytotoxicity From Ncb-0846 In The Treatment Of Triple Negative Breast Cancer

Harmantepe,

Dikicier,

Kocer

et al. 2024

Preprint

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BACKGROUND It was aimed to investigate the therapeutic effect of NCB-0846 inhibition of TNIK, which is the activator kinase of Wnt/β-catenin signaling pathway, on triple negative breast cancer at the molecular stage. METHODS MDA-MB-231 cells were used as triple negative breast cancer cell line and MCF-10A cells were used as control cell line. WST-1 analysis showed the cytotoxic effect of NCB-0846, Annexin V analysis showed its apoptotic effect, cell cycle analysis showed its effect on cell cycle, and Acridine Orange staining showed its effect on cell morphology. In addition, the effect of NCB-0846 on CTNNB1 (β-catenin) gene expression was demonstrated by RT-PCR analysis. RESULTS The viability rates in NCB-0846, MDA-MB-231 cells decreased significantly in a time and dose dependent manner (p < 0.01). The lowest viability rates for MDA-MB-231 cells were determined as 42,20% at the 3 µM dose after 72 hours of incubation. After 72 hours of incubation in MCF-10A cells, the viability rate was determined as 53,92% at 3 µM dose (p < 0.01). Apoptotic cell rates were determined as 60,5% and 39,33% for 3 µM NCB-0846 incubation in MDA-MB-231 and MCF-10A cells, respectively. In the RT-PCR analysis, while the expression level of CTNNB1 was decreased in MDA-MB-231 cells, it was determined that it increased significantly in MCF-10A cells. CONCLUSION NCB-0846 was shown to induce apoptosis while inhibiting viability in MDA-MB-231 cells. Our results suggest that NCB-0846 may be a suitable candidate for cancer therapy, but further in vitro and in vivo studies are required to better understand its mechanisms of action.

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“…Immunoblotting was performed as described previously [ 4 , 19 ]. The primary antibodies were used as follows: transforming growth factor-beta1 (TGF-β1, #ab179695, Abcam), connective-tissue growth factor (CTGF, #ab6992, Abcam), pro-interleukin-1beta (pro-IL-1β, #ab9722, Abcam), pro-IL-18 (#ab191860, Abcam), NOD-like receptor pyrin domain-containing protein 3 (NLRP3, #ab214185, Abcam), tumor necrosis factor-alpha (TNF-α, #ab205587), inducible nitric oxide synthase (iNOS, #ab178945), superoxide dismutase-2 (SOD2/MnSOD, #ab13534, Abcam), thioredoxin (TRX, #ab109385), thioredoxin-interacting protein (TXNIP, #ab188865), Parkin (#2132, Cell Signaling Technology), succinate dehydrogenase complex subunit A (SDHA, #ab66484, Abcam), C/EBP homologous protein (CHOP, L63F7, #2895, Cell Signaling), inositol-requiring protein-1α (IRE-1α, phospho S724, #ab37073, Abcam), B-cell lymphoma-2 (Bcl-2, #ab196495, Abcam), Bcl2-associated X (Bax, #ab32503, Abcam), p-JNK (#ab76572), p-MEK4 (#4514, Cell Signaling), p-ASK1 (#ab278547), p-P38 (#ab4822), p-MEK3 (#ab79586), beta actin (β-actin, #ab8226, Abcam).…”

Section: Methodsmentioning

confidence: 99%

The angiotensin receptor neprilysin inhibitor LCZ696 attenuates renal fibrosis via ASK1/JNK/p38 MAPK-mediated apoptosis in unilateral ureteral obstruction

Ding

Sheng

et al. 2023

PLoS ONE

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The angiotensin receptor neprilysin inhibitor LCZ696 affords superior cardioprotection and renoprotection compared with renin-angiotensin blockade monotherapy, but the underlying mechanisms remain elusive. Herein, we evaluated whether LCZ696 attenuates renal fibrosis by inhibiting ASK1/JNK/p38 mitogen-activated protein kinase (MAPK)-mediated apoptosis in a rat model of unilateral ureteral obstruction (UUO) and in vitro. Rats with UUO were treated daily for 7 days with LCZ696, valsartan, or the selective ATP competitive inhibitor of apoptosis signal-regulating kinase 1 (ASK1), GS-444217. The effects of LCZ696 on renal injury were examined by assessing the histopathology, oxidative stress, intracellular organelles, apoptotic cell death, and MAPK pathways. H2O2-exposed human kidney 2 (HK-2) cells were also examined. LCZ696 and valsartan treatment significantly attenuated renal fibrosis caused by UUO, and this was paralleled by downregulation of proinflammatory cytokines and decreased inflammatory cell influx. Intriguingly, LCZ696 had stronger effects on renal fibrosis and inflammation than valsartan. UUO-induced oxidative stress triggered mitochondrial destruction and endoplasmic reticulum stress, which resulted in apoptotic cell death; these effects were reversed by LCZ696. Both GS-444217 and LCZ696 hampered the expression of death-associated ASK1/JNK/p38 MAPKs. In H2O2-treated HK-2 cells, LCZ696 and GS-444217 increased cell viability but decreased the production of intracellular reactive oxygen species and MitoSOX and apoptotic cell death. Both agents also deactivated H2O2-stimulated activation of ASK1/JNK/p38 MAPKs. These findings suggest that LCZ696 protects against UUO-induced renal fibrosis by inhibiting ASK1/JNK/p38 MAPK-mediated apoptosis.

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Inhibition of RIP1-RIP3-mediated necroptosis attenuates renal fibrosis via Wnt3α/β-catenin/GSK-3β signaling in unilateral ureteral obstruction

Cited by 6 publications

References 31 publications

Protective Effects of Carnosol on Renal Interstitial Fibrosis in a Murine Model of Unilateral Ureteral Obstruction

Protective Effects of Carnosol on Renal Interstitial Fibrosis in a Murine Model of Unilateral Ureteral Obstruction

Determination Of Selective Cytotoxicity From Ncb-0846 In The Treatment Of Triple Negative Breast Cancer

The angiotensin receptor neprilysin inhibitor LCZ696 attenuates renal fibrosis via ASK1/JNK/p38 MAPK-mediated apoptosis in unilateral ureteral obstruction

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