Endoplasmic Reticulum Stress-Induced Autophagy Provides Cytoprotection from Chemical Hypoxia and Oxidant Injury and Ameliorates Renal Ischemia-Reperfusion Injury.

We examined whether endoplasmic reticulum (ER) stress-induced autophagy provides cytoprotection from renal tubular epithelial cell injury due to oxidants and chemical hypoxia in vitro, as well as from ischemia-reperfusion (IR) injury in vivo. We demonstrate that the ER stress inducer tunicamycin triggers an unfolded protein response, upregulates ER chaperone Grp78, and activates the autophagy pathway in renal tubular epithelial cells in culture. Inhibition of ER stress-induced autophagy accelerated caspase-3 activation and cell death suggesting a pro-survival role of ER stress-induced autophagy. Compared to wild-type cells, autophagy-deficient MEFs subjected to ER stress had enhanced caspase-3 activation and cell death, a finding that further supports the cytoprotective role of ER stress-induced autophagy. Induction of autophagy by ER stress markedly afforded cytoprotection from oxidants H2O2 and tert-Butyl hydroperoxide and from chemical hypoxia induced by antimycin A. In contrast, inhibition of ER stress-induced autophagy or autophagy-deficient cells markedly enhanced cell death in response to oxidant injury and chemical hypoxia. In mouse kidney, similarly to renal epithelial cells in culture, tunicamycin triggered ER stress, markedly upregulated Grp78, and activated autophagy without impairing the autophagic flux. In addition, ER stress-induced autophagy markedly ameliorated renal IR injury as evident from significant improvement in renal function and histology. Inhibition of autophagy by chloroquine markedly increased renal IR injury. These studies highlight beneficial impact of ER stress-induced autophagy in renal ischemia-reperfusion injury both in vitro and in vivo.

A Retrospective Survey Studying the Impact of Fabry Disease on Pregnancy.

Fabry disease (FD) is a lysosomal storage disorder resulting from a deficiency of lysosomal enzyme α-galactosidase A (α-gal A). Reduced or missing α-gal A enzyme results in the storage of globotriaosylceramide (GL3) and related glycosphingolipids in the cellular lysosomes throughout the body. The majority of GL3 buildup occurs in the body's vasculature resulting in narrowed blood vessels and an increased risk for strokes, transient ischemic attacks, and deep vein thrombosis. Theoretical concerns have been raised about increased pregnancy complications in women affected by FD as glycosphingolipid storage has been found in both maternal- and fetal-derived placental tissues. This retrospective study was conducted to better understand risks for women with FD during pregnancy. Survey questions included queries about prenatal medications, teratogenic exposures, prenatal testing, common pregnancy complications, Fabry symptoms during pregnancy, obstetrical history, and immediate neonatal history. In total, 41 affected women completed the survey. Results indicate several Fabry-related symptoms and features may worsen during pregnancy, including gastrointestinal symptoms, acroparesthesias, proteinuria, headaches, and postpartum depression. Although no life-threatening complications were reported, a statistically significant increased frequency of hypertension was observed when comparing data from this study to the general population (p < 0.05) and previous publications (p < 0.001). Limitations include sample size and recall bias. Though this survey sampling of women was small and required women to recall their past pregnancy experiences, the findings suggest that when pregnant, women with FD should be aware of potential worsening of FD symptoms and may benefit from consulting with a maternal-fetal medicine specialist.

A Case of False Negative NIPT for Down Syndrome-Lessons Learned.

Down syndrome or trisomy 21 is the most common cause of prenatal chromosome abnormalities with approximately 50% of all reported chromosome conditions. With the successful introduction of noninvasive prenatal testing (NIPT) for Down syndrome into routine prenatal care, it is important to understand the risks, benefits, and limitations in order to guide patients in making an informed decision. Herein, we describe the first published case report of a patient whose fetus tested "negative" for Trisomy 21 by NIPT but was diagnosed postnatally with trisomy 21. We present the importance of proper pretest and posttest genetic counseling to ensure prenatal patients are able to make informed decisions and are educated appropriately about NIPT.

zVAD-fmk prevents cisplatin-induced cleavage of autophagy proteins but impairs autophagic flux and worsens renal function.

Cisplatin injury to renal tubular epithelial cells (RTEC) is accompanied by autophagy and caspase activation. However, autophagy gradually decreases during the course of cisplatin injury. The role of autophagy and the mechanism of its decrease during cisplatin injury are not well understood. This study demonstrated that autophagy proteins beclin-1, Atg5, and Atg12 were cleaved and degraded during the course of cisplatin injury in RTEC and the kidney. zVAD-fmk, a widely used pancaspase inhibitor, blocked cleavage of autophagy proteins suggesting that zVAD-fmk would promote the autophagy pathway. Unexpectedly, zVAD-fmk blocked clearance of the autophagosomal cargo, indicating lysosomal dysfunction. zVAD-fmk markedly inhibited cisplatin-induced lysosomal cathepsin B and calpain activities and therefore impaired autophagic flux. In a mouse model of cisplatin nephrotoxicity, zVAD-fmk impaired autophagic flux by blocking autophagosomal clearance as revealed by accumulation of key autophagic substrates p62 and LC3-II. Furthermore, zVAD-fmk worsened cisplatin-induced renal dysfunction. Chloroquine, a lysomotropic agent that is known to impair autophagic flux, also exacerbated cisplatin-induced decline in renal function. These findings demonstrate that impaired autophagic flux induced by zVAD-fmk or a lysomotropic agent worsened renal function in cisplatin acute kidney injury (AKI) and support a protective role of autophagy in AKI. These studies also highlight that the widely used antiapoptotic agent zVAD-fmk may be contraindicated as a therapeutic agent for preserving renal function in AKI.