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. Although recovery can occur after one episode of cisplatin-induced AKI, longitudinal studies have indicated that multiple episodes of AKI lead to the development of chronic kidney disease, an irreversible disease with no current treatment. The standard mouse model of cisplatin-induced AKI consists of one high dose of cisplatin (>20 mg/kg) that is lethal to the animal 3 days later. This model does not accurately reflect the dosing regimen patients receive nor does it allow for the long-term study of kidney function and biology. We have developed a repeated dosing model whereby cisplatin is given once a week for 4 wk. Comparison of the repeated dosing model with the standard dosing model demonstrated that inflammatory cytokines and chemokines were induced in the repeated dosing model, but levels of cell death were lower in the repeated dosing model. The repeated dosing model had increased levels of fibrotic markers (fibronectin, transforming growth factor-β, and α-smooth muscle actin) and interstitial fibrosis. These data indicate that the repeated dosing model can be used to study the AKI to chronic kidney disease progression as well as the mechanisms of this progression.

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. Induction of ER stress with chemical modulators of ER homeostasis was sufficient to activate an EMT-like state in all cellular systems tested. Here, we provide evidence for the first time demonstrating that ER stress induces EMT that is neither cancer cell specific nor cell-type specific. In addition, we observed that chemotherapeutic drugs commonly used to treat patients also activate ER stress that is concomitant with activation of an EMT-like state. Interestingly, we find that following removal of ER stress, partial EMT characteristics still persist indicating that ER stress induced EMT is a long-term effect. Induction of mesenchymal characteristics, following chemotherapeutics treatment may be involved in providing cancer stemness and invasiveness in the cellular system. Interestingly, we find that mice treated with cisplatin have elevated level of ER stress and EMT markers in multiple tissues including lung, liver and kidneys. Furthermore, increased ER stress, as demonstrated by increased Bip, Chop, PDI, Ero1α and IRE1, and EMT, as demonstrated by increased Vimentin and Snail, is a hallmark of primary lung adenocarcinoma samples from patients. These observations have potential clinical relevance because overexpression of ER stress and EMT markers might contribute to chemoresistance and poor survival of lung adenocarcinoma patients.

. Inhibiting glucosylceramide synthase exacerbates cisplatin-induced acute kidney injury. J. Lipid Res. 2017. 58: 1439-1452. Supplementary key words ceramide • sphingolipids • apoptosis • inflammationAcute kidney injury (AKI) is a rapid decline in kidney function that occurs within hours to days of the initial kidney insult (1). The incidence of AKI is more than 5,000 cases per million per year for non-dialysis-requiring patients, while the incidence of AKI for dialysis-requiring patients is greater than 295 cases per million per year (1, 2). AKI complications are observed in 1-9% of hospital inpatients, with 40% of these patients being admitted to the intensive care unit due to AKI complications; more than 60% of patients in the intensive care unit have some sort of AKI episode during their stay, resulting in a 50-70% increased mortality rate (1,3,4). A common cause of AKI is nephrotoxic pharmacological agents, which account for 55-60% of hospital inpatient AKI cases (4). These agents include many antibiotics and anti-cancer chemotherapeutics. Abbreviations: AKI, acute kidney injury; aSMase, acid sphingomyelinase; BUN, blood urea nitrogen; CerS, ceramide synthase; CXCL1, chemokine (C-X-C motif) ligand 1; ER, endoplasmic reticulum; IL, interleukin; I/R, ischemia/reperfusion; KIM-1, kidney injury molecule-1; LTA, lectin from Tetragonolobus purpureus; MCP-1, monocyte chemotactic protein-1; PAS, periodic acid Schiff; PCNA, proliferating cell nuclear antigen; PDMP, D-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol; SCr, serum creatinine; S1P, sphingosine 1-phosphate; TBST, TBS with 0.1% Tween 20; TLR4, toll-like receptor 4. This work was supported by National Institute of Diabetes and Digestive and Kidney Diseases Grant R01-DK093462 (L.J.S.); National Institutes of Health Grants P30 CA138313 (A.B., J.B.), P20RR017677 (A.B., J.B.), UH2NS092981 (J.S.), 1R01HD076004-04 (J.S.), GM097741 (L.M.O.), and PO1CA097132 (L.M.O.); and Veterans Affairs Merit Awards 1I01BX002021-04 (J.S.) and CAMM-011-13S (L.M.O.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the

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Acute kidney injury (AKI) is the transient loss of renal function following an insult, such as nephrotoxicant exposure, sepsis, or ischemia. Numerous cell types play a role in the pathogenesis of AKI, including immune, endothelial, and renal proximal tubule cells. Our laboratory demonstrated that the beta‐2 adrenergic receptor (ADRB2) agonist formoterol accelerates the recovery of renal and mitochondrial function in mice following ischemia‐reperfusion injury (IRI). However, the cell type(s) responsible for this recovery remains unknown. To assess the role of renal proximal tubule cells in formoterol‐induced recovery of renal function, we generated a proximal tubule‐specific knockout of the ADRB2 receptor (γGT‐Cre: ADRB2Flox/Flox). Compared to controls (ADRB2Flox/Flox), renal cortical mRNA expression of the ADRB2 receptor was decreased 90% in γGT‐Cre:ADRB2Flox/Flox mice. These mice were subjected to renal IRI, followed by once daily dosing with 0.3 mg/kg formoterol or vehicle beginning at 24 h and euthanasia at 144 h. At 24 h following IRI, ADRB2Flox/Flox and γGT‐Cre: ADRB2Flox/Flox mice had a similar loss of renal function as measured by serum creatinine (0.89 mg/dL and 0.86 mg/dL, respectively). At 144 h following IRI, both ADRB2Flox/Flox and γGT‐Cre:ADRB2Flox/Flox mice treated with vehicle exhibited a modest but incomplete recovery of renal function as measured by serum creatinine (0.43 mg/dL and 0.46 mg/dL, respectively). These mice had similarly suppressed renal cortical mRNA and protein expression of markers of mitochondrial homeostasis such as NDUFB8, COX1, ATPSβ, and Mfn2. Following treatment with formoterol, ADRB2Flox/Flox mice exhibited accelerated recovery of renal function as measured by serum creatinine (0.20 mg/dL) with associated rescue of mitochondrial markers in the renal cortex. In contrast, formoterol did not enhance the recovery of renal function as measured by serum creatinine (0.39 mg/dL) or mitochondrial markers in γGT‐Cre:ADRB2Flox/Flox mice subjected to IRI. These data reveal that formoterol‐induced ADRB2 receptor activation on proximal tubule cells induces mitochondrial biogenesis and restores renal function following AKI. Support or Funding Information R.B.C. is supported by F30 DK104550 and T32 GM008716 (National Institutes of Health). W.S.G. is supported by T32 DK083262. R.G.S. is supported by R01 GM084147 (National Institutes of Health) and 1BX000851 (Department of Veterans Affairs). This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.