scholarly journals Renal proximal tubular NEMO plays a critical role in ischemic acute kidney injury

JCI Insight ◽  
2020 ◽  
Vol 5 (19) ◽  
Author(s):  
Sang Jun Han ◽  
Ryan M. Williams ◽  
Mihwa Kim ◽  
Daniel A. Heller ◽  
Vivette D’Agati ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Critical Role ◽  
Kidney Injury ◽  
Proximal Tubular ◽  
Ischemic Acute Kidney Injury ◽  
Renal Proximal Tubular

scholarly journals Canagliflozin protects against cisplatin-induced acute kidney injury by AMPK-mediated autophagy in renal proximal tubular cells

2022 ◽  
Vol 8 (1) ◽  
Author(s):  
Cheol Ho Park ◽  
Bin Lee ◽  
Myeonggil Han ◽  
Woo Joong Rhee ◽  
Man Sup Kwak ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Protective Effect ◽  
Kidney Injury ◽  
Proximal Tubular Cells ◽  
Cell Viability Assay ◽  
Tubular Cells ◽  
Compound C ◽  
Proximal Tubular ◽  
Renal Proximal Tubular Cells ◽  
Renal Proximal Tubular

AbstractSodium-glucose cotransporter 2 inhibitors, which are recently introduced as glucose-lowering agents, improve cardiovascular and renal outcomes in patients with diabetes mellitus. These drugs also have beneficial effects in various kidney disease models. However, the effect of SGLT2 inhibitors on cisplatin-induced acute kidney injury (AKI) and their mechanism of action need to be elucidated. In this study, we investigated whether canagliflozin protects against cisplatin-induced AKI, depending on adenosine monophosphate-activated protein kinase (AMPK) activation and following induction of autophagy. In the experiments using the HK-2 cell line, cell viability assay and molecular analysis revealed that canagliflozin protected renal proximal tubular cells from cisplatin, whereas addition of chloroquine or compound C abolished the protective effect of canagliflozin. In the mouse model of cisplatin-induced AKI, canagliflozin protected mice from cisplatin-induced AKI. However, treatment with chloroquine or compound C in addition to administration of cisplatin and canagliflozin eliminated the protective effect of canagliflozin. Collectively, these findings indicate that canagliflozin protects against cisplatin-induced AKI by activating AMPK and autophagy in renal proximal tubular cells.

scholarly journals Divergent roles for kidney proximal tubule and granulocyte PAD4 in ischemic AKI

2018 ◽  
Vol 314 (5) ◽  
pp. F809-F819 ◽  
Author(s):  
Hongmei Li ◽  
Sang Jun Han ◽  
Mihwa Kim ◽  
Ahyeon Cho ◽  
Yewoon Choi ◽  
...  
Keyword(s):  
Ischemia Reperfusion ◽  
Critical Role ◽  
Cell Lineage ◽  
Kidney Injury ◽  
Myeloid Cell ◽  
Neutrophil Infiltration ◽  
Proximal Tubular ◽  
Renal Proximal Tubular ◽  
Renal Tubular ◽  
Deficient Mice

We previously demonstrated that kidney peptidylarginine deiminase-4 (PAD4) plays a critical role in ischemic acute kidney injury (AKI) in mice by promoting renal tubular inflammation and neutrophil infiltration (Ham A, Rabadi M, Kim M, Brown KM, Ma Z, D’Agati V, Lee HT. Am J Physiol Renal Physiol 307: F1052–F1062, 2014). Although the role of PAD4 in granulocytes including neutrophils is well known, we surprisingly observed profound renal proximal tubular PAD4 induction after renal ischemia-reperfusion (I/R) injury. Here we tested the hypothesis that renal proximal tubular PAD4 rather than myeloid-cell lineage PAD4 plays a critical role in exacerbating ischemic AKI by utilizing mice lacking PAD4 in renal proximal tubules (PAD4ff PEPCK Cre mice) or in granulocytes (PAD4ff LysM Cre mice). Mice lacking renal proximal tubular PAD4 were significantly protected against ischemic AKI compared with wild-type (PAD4ff) mice. Surprisingly, mice lacking PAD4 in myeloid cells were also protected against renal I/R injury although this protection was less compared with renal proximal tubular PAD4-deficient mice. Renal proximal tubular PAD4-deficient mice had profoundly reduced renal tubular apoptosis, whereas myeloid-cell PAD4-deficient mice showed markedly reduced renal neutrophil infiltration. Taken together, our studies suggest that both renal proximal tubular PAD4 as well as myeloid-cell lineage PAD4 play a critical role in exacerbating ischemic AKI. Renal proximal tubular PAD4 appears to contribute to ischemic AKI by promoting renal tubular apoptosis, whereas myeloid-cell PAD4 is preferentially involved in promoting neutrophil infiltration to the kidney and inflammation after renal I/R.

scholarly journals Perilipin 2 Impacts Acute Kidney Injury via Regulation of PPARα

2021 ◽  
Vol 2021 ◽  
pp. 1-12
Author(s):  
Sujuan Xu ◽  
Edward Lee ◽  
Zhaoxing Sun ◽  
Xiaoyan Wang ◽  
Ting Ren ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Hydrogen Peroxide ◽  
Acute Kidney Injury ◽  
Ischemia Reperfusion ◽  
Kidney Injury ◽  
Renal Tumors ◽  
Tubular Cells ◽  
Proximal Tubular ◽  
Perilipin 2 ◽  
Renal Proximal Tubular

Renal ischemia-reperfusion (I/R) can induce oxidative stress and injury via the generation of reactive oxygen species (ROS). Renal proximal tubular cells are susceptible to oxidative stress, and the dysregulation of renal proximal tubular cellular homeostasis can damage cells via apoptotic pathways. A recent study showed that the generation of ROS can increase perilipin 2 (Plin2) expression in HepG2 cells. Some evidence has also demonstrated the association between Plin2 expression and renal tumors. However, the underlying mechanism of Plin2 in I/R-induced acute kidney injury (AKI) remains elusive. Here, using a mouse model of I/R-induced AKI, we found that ROS generation was increased and the expression of Plin2 was significantly upregulated. An in vitro study further revealed that the expression of Plin2, and the generation of ROS were significantly upregulated in primary tubular cells treated with hydrogen peroxide. Accordingly, Plin2 knockdown decreased apoptosis in renal proximal tubular epithelial cells treated with hydrogen peroxide, which depended on the activation of peroxisome proliferator-activated receptor α (PPARα). Overall, the present study demonstrated that Plin2 is involved in AKI; knockdown of this marker might limit apoptosis via the activation of PPARα. Consequently, the downregulation of Plin2 could be a novel therapeutic strategy for AKI.

scholarly journals Edaravone-Loaded Mesoscale Nanoparticles Treat Cisplatin-Induced Acute Kidney Injury

2020 ◽  
Author(s):  
Ryan M. Williams ◽  
Janki Shah ◽  
Elizabeth Mercer ◽  
Helen S. Tian ◽  
Justin M. Cheung ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Acute Kidney Injury ◽  
Epithelial Cells ◽  
Kidney Injury ◽  
Tubular Epithelial Cells ◽  
Co Morbidity ◽  
Proximal Tubular Epithelial Cells ◽  
Proximal Tubular ◽  
Tumor Accumulation ◽  
Renal Proximal Tubular

AbstractCisplatin-induced acute kidney injury (CI-AKI) is a significant co-morbidity of chemotherapeutic regimens. While this condition is associated with substantially lower survival and increased economic burden, there is no pharmacological agent to effectively treat CI-AKI. The disease is hallmarked by acute tubular necrosis of the proximal tubular epithelial cells primarily due to increased oxidative stress. In our prior work, we developed a highly-selective kidney-targeted mesoscale nanoparticle (MNP) that accumulates primarily in the renal proximal tubular epithelial cells while exhibiting no toxicity. Here, we found that MNPs exhibit renal-selective targeting in multiple mouse models of tumor growth with virtually no tumor accumulation. We then evaluated the therapeutic efficacy of MNPs loaded with the reactive oxygen species scavenger edaravone in a mouse model of CI-AKI. We found a marked and significant therapeutic effect with this approach as compared to free drug or empty control MNPs, including improved renal function, histology, and diminution of oxidative stress. These results indicated that renal-selective MNP edaravone delivery holds substantial potential in the treatment of acute kidney injury among patients undergoing cisplatin-based chemotherapy.

scholarly journals A Novel Renoprotective Strategy: Upregulation of PD-L1 Mitigates Cisplatin-Induced Acute Kidney Injury

2021 ◽  
Vol 22 (24) ◽  
pp. 13304
Author(s):  
Jun Liu ◽  
David C. Yang ◽  
Jun Zhang ◽  
Ssu-Wei Hsu ◽  
Robert H. Weiss ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Immune Checkpoint ◽  
Animal Studies ◽  
Kidney Injury ◽  
Checkpoint Protein ◽  
Protein Levels ◽  
Programmed Death ◽  
Proximal Tubular Epithelial Cells ◽  
Proximal Tubular ◽  
Renal Proximal Tubular

The innate and adaptive immunities have been documented to participate in the pathogenesis of nephrotoxic acute kidney injury (AKI); however, the mechanisms controlling these processes have yet to be established. In our cisplatin-induced AKI mouse model, we show pathological damage to the kidneys, with the classical markers elevated, consistent with the response to cisplatin treatment. Through assessments of the components of the immune system, both locally and globally, we demonstrate that the immune microenvironment of injured kidneys was associated with an increased infiltration of CD4+ T cells and macrophages concomitant with decreased Treg cell populations. Our cell-based assays and animal studies further show that cisplatin exposure downregulated the protein levels of programmed death-ligand 1 (PD-L1), an immune checkpoint protein, in primary renal proximal tubular epithelial cells, and that these inhibitions were dose-dependent. After orthotopic delivery of PD-L1 gene into the kidneys, cisplatin-exposed mice displayed lower levels of both serum urea nitrogen and creatinine upon PD-L1 expression. Our data suggest a renoprotective effect of the immune checkpoint protein, and thereby provide a novel therapeutic strategy for cisplatin-induced AKI.

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