Endoplasmic reticulum stress induces epithelial-mesenchymal transition through autophagy via activation of c-Src kinase.

BACKGROUND: Endoplasmic reticulum (ER) stress has been implicated in inducing epithelial-mesenchymal transition (EMT). ER stress is also known to induce autophagy. However, it is unclear whether ER stress-induced autophagy contributes to EMT. We hypothesized that ER stress might induce EMT through autophagy via activation of c-Src kinase in tubular epithelial cells. METHOD: All experiments were performed using HK-2 cells. Protein expression was measured by Western blot analysis. Immunofluorescence and small interfering RNA (siRNA) experiments were performed. RESULTS: Chemical ER stress inducers such as tunicamycin (TM, 0.2 µM) and thapsigargin (TG, 0.2 µM) induced EMT, as shown by upregulation of α-smooth muscle actin and downregulation of E-cadherin. ER stress inhibitors such as 4-PBA and salubrinal suppressed both TM- and TG-induced EMT. TM and TG also induced autophagy, as evidenced by upregulation of LC3-II and beclin-1, which were abolished by pretreatment with ER stress inhibitors. Transfection with siRNA targeting ER stress protein (IRE-1) blocked the TM- or TG-induced EMT and autophagy. Autophagy inhibitors such as 3-methyladenine and bafilomycin inhibited the TM- or TG-induced EMT. Transfection with siRNA targeting autophagy protein (beclin-1) also blocked the TM- or TG-induced EMT. Both TM and TG induced activation of c-Src kinase. Inhibitor of c-Src kinase (PP2) suppressed the TM- or TG-induced autophagy and EMT. CONCLUSION: ER stress by TM or TG induced EMT through autophagy via activation of c-Src kinase in tubular epithelial cells.

Kidney transplantation alone in end-stage renal disease patients with hepatitis B liver cirrhosis: a single-center experience.

BACKGROUND: Kidney transplantation (KT) alone in end-stage renal disease (ESRD) patients with hepatitis B virus liver cirrhosis (LC) is controversial. This study compared outcomes of KT in hepatitis B surface antigen-positive patients with ESRD with (LC group) and without LC (non-LC group). METHODS: Outcomes were analyzed in 103 hepatitis B surface antigen-positive patients with ESRD who underwent KT alone between 1997 and 2011. Ninety-one were in the non-LC group and 12 were in the LC group. Of the latter, eight were Child-Pugh (CP) class A and four were CP class B. RESULTS: Baseline aspartate transaminase and alanine transaminase levels were higher in the LC group. model for end-stage liver disease (MELD) scores were similar in patients with CP class A and class B, only serum albumin level was lower in CP class B. After KT, one CP class A patient showed an increase in the CP score from 5 to 10 points, MELD score from 22.3 to 44.1 points. The CP and MELD scores of the other 11 patients in the LC group did not increase. All four pre-KT CP class B patients were reclassified as class A after KT because of elevated serum albumin levels. Four patients in the LC group developed hepatocellular carcinoma at a median of 35 months (range, 20-57 months) after KT. The 5-year patient survival rate was similar in the LC and non-LC groups (100% vs. 94%, P=0.15). The incidence of pre-KT LC did not differ between survivors and nonsurvivors (11% vs. 18%, P=0.61). Occurrence of hepatocellular carcinoma was significantly higher in nonsurvivors than in survivors. CONCLUSION: Kidney transplantation alone may be safe in patients with compensated hepatitis B virus LC.