Fat atrophy and adipose tissue inflammation can cause the pathogenesis of metabolic symptoms in chronic kidney disease (CKD). During CKD, the serum levels of advanced oxidation protein products (AOPPs) are elevated. However, the relationship between fat atrophy/adipose tissue inflammation and AOPPs has remained unknown. The purpose of this study was to investigate the involvement of AOPPs, which are known as uremic toxins, in adipose tissue inflammation and to establish the underlying molecular mechanism. In vitro studies involved co-culturing mouse-derived adipocytes (differentiated 3T3-L1) and macrophages (RAW264.7). In vivo studies were performed using adenine-induced CKD mice and AOPP-overloaded mice. Fat atrophy, macrophage infiltration and increased AOPP activity in adipose tissue were identified in adenine-induced CKD mice. AOPPs induced MCP-1 expression in differentiated 3T3-L1 adipocytes via ROS production. However, AOPP-induced ROS production was suppressed by the presence of NADPH oxidase inhibitors and the scavengers of mitochondria-derived ROS. A co-culturing system showed AOPPs induced macrophage migration to adipocytes. AOPPs also up-regulated TNF-α expression by polarizing macrophages to an M1-type polarity, and then induced macrophage-mediated adipose inflammation. In vitro data was supported by experiments using AOPP-overloaded mice. AOPPs contribute to macrophage-mediated adipose inflammation and constitute a potential new therapeutic target for adipose inflammation associated with CKD.
Parathyroid
hormone-related protein (PTHrP), which is secreted
from a tumor, contributes to the progression of cachexia, a condition
that is observed in half of all cancer patients. Although drug clearance
was reported to decrease in patients with cancer cachexia, the details
have not been clarified. The present study reports on an investigation
of whether PTHrP is involved in the alternation of drug metabolism
in cases of cancer cachexia. Cancer cachexia model rats with elevated
serum PTHrP levels showed a significant decrease in hepatic and intestinal
CYP3A2 protein expression. When midazolam, a CYP3A substrate drug,
was administered intravenously or orally to the cancer cachexia rats,
its area under the curve (AUC) was increased by about 2 and 5 times,
as compared to the control group. Accordingly, the bioavailability
of midazolam was increased by about 3 times, thus enhancing its pharmacological
effect. In vitro experiments using HepG2 cells and Caco-2 cells showed
that the addition of serum from cancer cachexia rats or active PTHrP
(1–34) to each cell resulted in a significant decrease in the
expression of CYP3A4 mRNA. Treatment with a cell-permeable cAMP analog
also resulted in a decreased CYP3A4 expression. Pretreatment with
protein kinase A (PKA), protein kinase C (PKC), and nuclear factor-kappa
B (NF-κB) inhibitors recovered the decrease in CYP3A4 expression
that was induced by PTHrP (1–34). These results suggest that
PTHrP suppresses CYP3A expression via the cAMP/PKA/PKC/NF-κB
pathway. Therefore, it is likely that PTHrP would be involved in the
changes in drug metabolism observed in cancer cachexia.
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