Abstract
Hypergravity conditions may subject the kidney to intrinsic stress and lead to hemodynamic kidney dysfunction. However, the mechanisms underlying this phenomenon remain unclear. Accumulation of unfolded proteins in the endoplasmic reticulum (i.e., ER stress) is often observed in kidney diseases. Therefore, this study investigated whether hypergravity stress alters acetaminophen-induced renal toxicity in vivo, as well as the molecular mechanisms involved in this process. C57BL/6 mice were submitted to one or three loads of +9 Gx hypergravity for 1 h with or without acetaminophen (APAP) treatment. The protein levels of cell survival markers, including pAKT and pCREB, were decreased in the kidney after acetaminophen treatment with a single hypergravity load. Additionally, the combined treatment increased kidney injury markers, serum creatinine, and Bax, Bcl2, and Kim-1 transcript levels and enhanced ER stress-related markers were further. Moreover, multiple hypergravity loads enabled mice to overcome kidney injury, as indicated by decreases in serum creatinine content and ER stress marker levels, along with increased cell viability indices. Similarly, multiple hypergravity loads plus APAP elevated miR-122 levels in the kidney, which likely originated from the liver, as the levels of primary miR-122 increased only in the liver and not the kidney. Importantly, this phenomenon may contribute to overcoming hypergravity-induced kidney injury. Taken together, our results demonstrate that APAP-exposed mice submitted to a single load of hypergravity exhibited more pronounced kidney dysfunction due to increased ER stress, which may be overcome by repetitive hypergravity loads presumably due to increased production of miR-122 in the liver. Thus, our study provides novel insights into the mechanisms by which hypergravity stress plus APAP medication induce kidney injury, which may be overcome by repeated hypergravity exposure.
Highlights
Since the beginning of manned space missions in 1961, technological advancement has reached a point where space travel has become within reach of civilians and trained astronauts alike (e.g., Space-X project) [1,2]
Kidney Injury Associated with a Single Hypergravity Load Coupled with APAP Treatment
Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining and hematoxylin and eosin (H&E) staining analyses revealed an increased intensity of TUNEL-positive cells and disorganized tubular epithelium cells in mice exposed to a single hypergravity load coupled with APAP treatment, compared to hypergravity or APAP treatment alone (Figure 1B)
Summary
Since the beginning of manned space missions in 1961, technological advancement has reached a point where space travel has become within reach of civilians and trained astronauts alike (e.g., Space-X project) [1,2]. Despite recent technological advances and prospects, many factors, such as gravitational changes, ionizing radiation, and physiological/psychological stressors, threaten the health of astronauts outside of the. The effects of gravitational changes associated with space flight on living organisms remain poorly documented due to a lack of ground-based facilities and experimental limitations. The greatest gravitational change that living organisms experience during escape and re-entry into the Earth’s atmosphere is the high gravity applied during the ascent of the launch vehicle and the rapid change to weightlessness experienced thereafter. The gravity-associated stress experienced by living organisms varies depending on the research model, object, and observation index. A systematic approach is required to facilitate data interpretation and ensure compatibility
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