ABSTRACT
PURPOSE: Tumor growth factor-beta1 (TGF-beta1) plays a pivotal role in processes like kidney epithelial-mesenchymal transition (EMT) and interstitial fibrosis, which correlate well with progression of renal disease. Little is known about underlying mechanisms that regulate EMT. Based on the anatomical relationship between erythropoietin (EPO)-producing interstitial fibroblasts and adjacent tubular cells, we investigated the role of EPO in TGF-beta1-mediated EMT and fibrosis in kidney injury. METHODS: We examined apoptosis and EMT in TGF-beta1-treated LLC-PK1 cells in the presence or absence of EPO. We examined the effect of EPO on TGF-beta1-mediated Smad signaling. Apoptosis and cell proliferation were assessed with flow cytometry and hemocytometry. We used Western blotting and indirect immunofluorescence to evaluate expression levels of TGF-beta1 signal pathway proteins and EMT markers. RESULTS: We demonstrated that ZVAD-FMK (a caspase inhibitor) inhibited TGF-beta1-induced apoptosis but did not inhibit EMT. In contrast, EPO reversed TGF-beta1-mediated apoptosis and also partially inhibited TGF-beta1-mediated EMT. We showed that EPO treatment suppressed TGF-beta1-mediated signaling by inhibiting the phosphorylation and nuclear translocation of Smad 3. Inhibition of mitogen-activated protein kinase kinase 1 (MEK 1) either directly with PD98059 or with MEK 1 siRNA resulted in inhibition of EPO-mediated suppression of EMT and Smad signal transduction in TGF-beta1-treated cells. CONCLUSIONS: EPO inhibited apoptosis and EMT in TGF-beta1-treated LLC-PK1 cells. This effect of EPO was partially mediated by a mitogen-activated protein kinase-dependent inhibition of Smad signal transduction.
Subject(s)
Epithelium/drug effects , Erythropoietin/pharmacology , Kidney/drug effects , Mesoderm/drug effects , Mitogen-Activated Protein Kinase Kinases/physiology , Smad Proteins/antagonists & inhibitors , Amino Acid Chloromethyl Ketones/pharmacology , Animals , Apoptosis/drug effects , Caspase Inhibitors , Caspases/metabolism , Cell Line , Cell Proliferation/drug effects , Cysteine Proteinase Inhibitors/pharmacology , Down-Regulation/drug effects , Epithelium/physiology , Kidney/metabolism , Kidney/physiology , Kidney Tubules, Proximal/drug effects , Kidney Tubules, Proximal/metabolism , Kidney Tubules, Proximal/physiology , Mesoderm/physiology , Mitogen-Activated Protein Kinase Kinases/metabolism , Signal Transduction/drug effects , Smad Proteins/metabolism , Smad Proteins/physiology , Swine , Transforming Growth Factor beta1/antagonists & inhibitors , Transforming Growth Factor beta1/pharmacologySubject(s)
Anti-Bacterial Agents/adverse effects , Bartter Syndrome/chemically induced , Bartter Syndrome/diagnosis , Gentamicins/adverse effects , Anti-Bacterial Agents/therapeutic use , Female , Gentamicins/therapeutic use , Humans , Middle Aged , Treatment Outcome , Urinary Tract Infections/drug therapyABSTRACT
We report a case of nephrotic syndrome and acute renal failure apparently induced by sunitinib. A 67-year-old man with a history of metastatic renal cell carcinoma presented with progressive kidney dysfunction with proteinuria, general edema, and body weight gain of 21 kg after undergoing 3 weeks of sunitinib therapy. The patient had taken no other over-the-counter medications, and all other possible causes of nephrotic syndrome were excluded. The Naranjo Adverse Drug Reaction Probability Scale score for this event was 6, indicating a high probability that the observed presentations were associated with use of the drug. However, despite the discontinuation of sunitinib, his condition deteriorated, and hemodialysis was initiated for respiratory distress. A renal biopsy was performed, which revealed ischemic acute tubular necrosis with minimal change nephropathy. In conclusion, nephrologists and oncologists should be aware that nephrotic syndrome with ischemic acute tubular necrosis is a possible adverse effect of sunitinib. For early diagnosis of this condition and to avoid renal damage, we recommend differential diagnosis of serum creatinine and proteinuria in patients undergoing sunitinib therapy.
