Upregulation of NADH/NADPH oxidase 4 by angiotensin II induces podocyte apoptosis

Angiotensin II induces glomerular and podocyte injury via systemic and local vasoconstrictive or non-hemodynamic effects including oxidative stress. The release of reactive oxygen species (ROS) from podocytes may participate in the development of glomerular injury and proteinuria. We studied the role of oxidative stress in angiotensin II-induced podocyte apoptosis. Methods: Mouse podocytes were incubated in media containing various concentrations of angiotensin II at different incubation times and were transfected with NADH/NADPH oxidase 4 (Nox4) or angiotensin II type 1 receptor for 24 hours. The changes in intracellular and mitochondrial ROS production and podocyte apoptosis were measured according to the presence of angiotensin II. Results: Angiotensin II increased the generation of mitochondrial superoxide anions and ROS levels but suppressed superoxide dismutase activity in a dose- and time-dependent manner that was reversed by probucol, an antioxidant. Angiotensin II increased Nox4 protein and expression by a transcriptional mechanism that was also reversed by probucol. In addition, the suppression of Nox4 by small interfering RNA (siRNA) reduced the oxidative stress induced by angiotensin II. Angiotensin II treatment also upregulated AT1R protein. Furthermore, angiotensin II promoted podocyte apoptosis, which was reduced significantly by probucol and Nox4 siRNA and also recovered by angiotensin II type 1 receptor siRNA. Conclusion: Our findings suggest that angiotensin II increases the generation of mitochondrial superoxide anions and ROS levels via the upregulation of Nox4 and angiotensin II type 1 receptor. This can be prevented by Nox4 inhibition and/or antagonizing angiotensin II type 1 receptor as well as use of antioxidants.

Erratum: Puromycin aminonucleoside triggers apoptosis in podocytes by inducing endoplasmic reticulum stress Volume 37, Issue 3, September 2018, Pages 210–221

The authors would like to publish this corrigendum to correct the spells of an author's name in the above article.

Puromycin aminonucleoside triggers apoptosis in podocytes by inducing endoplasmic reticulum stress

BACKGROUND: Puromycin aminonucleoside (PAN) is a known podocytotoxin. PAN-induced nephrosis is a widely used animal model for studying human idiopathic nephrotic syndrome. Abnormal protein accumulation associated with podocyte-specific endoplasmic reticulum (ER) stress damages cells structurally and functionally, which in turn induces apoptosis and severe proteinuria. In the present study, we investigated the effect of PAN on ER stress and apoptosis in podocytes in vitro. METHODS: Mouse podocytes were cultured and treated with various concentrations of PAN. ER stress markers were then evaluated by western blotting, and apoptosis was evaluated by fluorescence-activated cell sorting (FACS) and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assays. RESULTS: PAN treatment increased ER stress markers such as activating transcription factor (ATF) 6α and caspase-12 in a dose-dependent manner at 12 and 24 hours, respectively. These markers were reduced by chemical chaperones, such as sodium 4-phenylbutyric acid and tauroursodeoxycholic acid. PAN treatment also increased 78 kD glucose-regulated protein (GRP78)/binding immunoglobulin protein (BiP) at the earlier stage of 12 hours. PAN significantly induced podocyte apoptosis in concentration- and time-dependent manners, as seen using FACS and TUNEL assays. This result was improved by Nox4 siRNA, ATF6 siRNA, and chemical chaperones. LY294002, a PI3-kinase inhibitor, significantly boosted ER stress and apoptosis. PAN-induced ER stress increased oxidative stress and subsequently induced apoptosis, and could be mitigated by inhibition of PI3-kinase signaling. CONCLUSION: Our findings suggest that PAN induces ER stress in podocytes mainly through the GRP78/BiP, ATF6α, and caspase-12 pathways, which trigger apoptosis via induction of oxidative stress. This stress is mitigated by inhibiting PI3-kinase signaling.

Evaluation of Oral Thymomodulin Effect on the Patients with Chronic Viral Hepatitis B / 대한간학회지

BACKGROUND/AIMS: As one of biological modifiers of immune reaction, thymomodulin is known to be peptide derivatives of thyrnic acid. Lysate, and thymomodulin can stimulate antibody formations by increasmg the functions of B and T tymphocytes. Furthermore, GM-CSF and TNF can be released by thymomodulin resulting in relief from bone marrow suppression. And these actions of thymomodulin affer a new therapeutic modality in chronic diseases ot the liver as well as chronic hronchitis. Although interferons are frequently under trials for chronic viral hepatitis B. anothersome of side etTec ts and cost effectiveness is often refractory to be used. Herein, this study was intended to estimate the effectiveness and side effects of per oral thymomodulin. METHODS: Forty one patients with chronic viral hepatitis showing positivity of HBsAg over 6 months were treated with per oral thymomodulin (15mlAmg/ml, h vice daily, over 6 months), Clinical data of preand post-trial states were prospectively investigated. RESULTS: As a result, negative conversion of HBV DNA izvealed 20.6% out ol 34 patients showed HBsAg positivity. HBeAg was isappeared in 10.4 % among the 29 cases. Only two cases were shown the clearance of HBsAg. However. These data are statistically insignificant in comparison to the control group (p>0.05, chi-square test). The desirable effects were noticed as disappearance of acne in 5 cases, and amelioration of menstrual abnormalities in 3 cases. Undesirable side effects were only mild nausea in 3 cases, and indigestion in 2 cases. CONCLUSIONS: On thc basis of these data, it is suggested that oral thymomodulin is an easy and safe therapeutic approach in chronic viral hepatitis B but remains to be heralded by long-term clinical trials.