Neutral ceramidase deficiency protects against cisplatin-induced acute kidney injury.

Cisplatin is a commonly used chemotherapeutic for the treatment of many solid organ cancers; however, its effectiveness is limited by the development of acute kidney injury (AKI) in 30% of patients. AKI is driven by proximal tubule cell death, leading to rapid decline in renal function. It has previously been shown that sphingolipid metabolism plays a role in regulating many of the biological processes involved in cisplatin-induced AKI.

The 5-hydroxytryptamine receptor 1F stimulates mitochondrial biogenesis and angiogenesis in endothelial cells.

A hallmark of acute kidney injury (AKI) is vascular rarefication and mitochondrial dysfunction. Promoting vascular recovery following AKI could facilitate kidney repair as the vasculature is responsible for oxygen and nutrient delivery to extravascular tissues. Little is known about mitochondrial biogenesis (MB) in endothelial cells, and the role of 5-HT receptor signaling in MB has only been studied in epithelial cells.

Loss of the Na/H Exchange Regulatory Factor 1 Increases Susceptibility to Cisplatin-Induced Acute Kidney Injury.

Na/H exchange regulatory cofactor (NHERF)-1, a scaffolding protein, anchors multiple membrane proteins in renal proximal tubules. Cultured proximal tubule cells deficient in Nherf1 and proximal tubules from Nherf1-deficient mice exhibit aberrant trafficking. Nherf1-deficient cells also exhibit an altered transcription pattern and worse survival.

Proximal Tubule -Adrenergic Receptor Mediates Formoterol-Induced Recovery of Mitochondrial and Renal Function after Ischemia-Reperfusion Injury.

Acute kidney injury (AKI) is the rapid loss of renal function after an insult, and renal proximal tubule cells (RPTCs) are central to the pathogenesis of AKI. The -adrenergic receptor ( AR) agonist formoterol accelerates the recovery of renal function in mice after ischemia-reperfusion injury (IRI) with associated rescue of mitochondrial proteins; however, the cell type responsible for this recovery remains unknown. The role of RPTCs in formoterol-induced recovery of renal function was assessed in a proximal tubule-specific knockout of the AR (GT-Cre:ADRB2).

Moderate aging does not exacerbate cisplatin-induced kidney injury or fibrosis despite altered inflammatory cytokine expression and immune cell infiltration.

Aging is a risk factor for certain forms of kidney injury due to normal physiological changes, but the role of aging in cisplatin-induced kidney injury is not well defined in humans or animal models of the disease. To improve on current knowledge in this field, we treated 8- and 40-wk-old FVB/n mice with one high dose of cisplatin as a model of acute kidney injury or with repeated low doses of cisplatin (7 mg/kg cisplatin once a week for 4 wk) as a clinically relevant model of chronic kidney disease to determine if aging exacerbates cisplatin-induced kidney injury. Levels of acute kidney injury were comparable in 8- and 40-wk-old mice.

The role of sphingolipids in acute kidney injury.

Acute kidney injury (AKI) is most simply defined as the rapid loss of kidney function in a matter of hours to days. AKI can manifest in a number of ways including pre-renal, post-renal, or intrinsic AKI. During acute kidney injury, multiple pathogenic processes are activated including inflammation, cell death, and the generation of reactive oxygen species, just to name a few.

Inhibiting glucosylceramide synthase exacerbates cisplatin-induced acute kidney injury.

Acute kidney injury (AKI), resulting from chemotherapeutic agents such as cisplatin, remains an obstacle in the treatment of cancer. Cisplatin-induced AKI involves apoptotic and necrotic cell death, pathways regulated by sphingolipids such as ceramide and glucosylceramide. Results from this study indicate that C57BL/6J mice treated with cisplatin had increased ceramide and hexosylceramide levels in the renal cortex 72 h following cisplatin treatment.

Common cytotoxic chemotherapeutics induce epithelial-mesenchymal transition (EMT) downstream of ER stress.

Endoplasmic reticulum (ER) in eukaryotes is a main organelle involved in a wide variety of functions including calcium storage, lipid biosynthesis, protein folding and protein transport. Disruption of ER homeostasis leads to ER stress and activation of the unfolded protein response (UPR). We and others have previously found that ER stress induces EMT in different cellular systems.

Repeated administration of low-dose cisplatin in mice induces fibrosis.

Cisplatin, a chemotherapeutic used for the treatment of solid cancers, has nephrotoxic side effects leading to acute kidney injury (AKI). Cisplatin cannot be given to patients that have comorbidities that predispose them to an increased risk for AKI. Even without these comorbidities, 30% of patients administered cisplatin will develop kidney injury, requiring the oncologist to withhold or reduce the next dose, leading to a less effective therapeutic regimen.

Suramin protects from cisplatin-induced acute kidney injury.

Cisplatin, a commonly used cancer chemotherapeutic, has a dose-limiting side effect of nephrotoxicity. Approximately 30% of patients administered cisplatin suffer from kidney injury, and there are limited treatment options for the treatment of cisplatin-induced kidney injury. Suramin, which is Federal Drug Administration-approved for the treatment of trypanosomiasis, improves kidney function after various forms of kidney injury in rodent models.

Targeting of BRAF resistant melanoma via extracellular matrix metalloproteinase inducer receptor.

Background: The BRAF inhibitor vemurafenib (PLX) has shown promise in treating metastatic melanoma, but most patients develop resistance to treatment after 6 mo. We identified a transmembrane protein, extracellular matrix metalloproteinase inducer (EMMPRIN) as a cell surface receptor highly expressed by PLX-resistant melanoma. Using an S100A9 ligand, we created an EMMPRIN targeted probe and liposome that binds to melanoma cells in vivo, thus designing a novel drug delivery vehicle.