Project description:Akkermansia muciniphila (Akk) associated with multiple metabolic diseases and administration of Akk can improve the metabolic disorders. However, little is known about the effect of Akk on jejunal epithelial cells which absorb lipid and interact with oral administrated Akk. We oral administrated Akk to mice and measured the lipid absorption and gene expression in small intestinal epithelial cells. The long-term effect of Akk treatment reduced lipid deposits in the liver and adipocytes with improved the glucose metabolism. This is particularly caused by reduced lipid absorption in jejunal epithelia. Akk feeding reduced the expression of those genes that regulate synthesis and cell cycles, characters of the host cell responding to energy deficiency. In fact, we detected increased AMPK-alpha phosphorylation levels in Akk-treated jejunal epithelial cells both in vivo and in vitro. Furthermore, activating AMPK inhibits lipids absorption in jejunum. Thus, we conclude that oral administration of Akk activates the AMPK pathway and represses the lipid absorption in jejunal epithelial cells, which contributes to the metabolic benefits of oral Akk administration.
Project description:Doxorubicin (DOX) is considered as the major culprit in chemotherapy-induced cardiotoxicity, which limits its clinical application. Akkermansia muciniphila (AKK) shows a beneficial role as a probiotic in the treatment of metabolic syndrome. However, the changes of AKK during DIC and whether it mediates cardioprotective effects remains unclear. Cardiac transcriptomics certified by in vitro experiments demonstrated that AKK administration effectively improved mitochondrial function and alleviated DIC, by activation of PPARα/PGC1α signaling pathway. These findings provide a therapeutic strategy for DIC through supplementation with AKK.
Project description:16S rRNA sequencing showed that Akkermansia muciniphila (Akk) decreased during the course of HCC tumor development, and daily administration of Akk not only ameliorated liver steatosis and cholesterol biosynthesis but also effectively attenuated the development of NAFLD-induced HCC.
Project description:Neuropilin-1 (NRP1), a co-receptor for various cytokines, including TGF-β, has been identified as a potential therapeutic target for fibrosis. However, its role and mechanism in renal fibrosis remains elusive. Here, we show that NRP1 is upregulated in distal tubular (DT) cells of patients with transplant renal insufficiency and mice with renal ischemia-reperfusion (I-R) injury. Knockout of Nrp1 reduced multiple endpoints of renal injury and fibrosis. We found that Nrp1 facilitates the binding of TNF-α to its receptor in DT cells after renal injury. This signaling results in a downregulation of lysine crotonylation of the metabolic enzyme Cox4i1, decreased cellular energetics and exacerbation of renal injury. Furthermore, by single-cell RNA-sequencing we found that Nrp1-positive DT cells secrete collagen and communicate with myofibroblasts, exacerbating acute kidney injury (AKI)-induced renal fibrosis by activating Smad3. Dual genetic deletion of Nrp1 and Tgfbr1 in DT cells better improves renal injury and fibrosis than either single knockout. Together, these results reveal that targeting of NRP1 represents a promising strategy for the treatment of AKI and subsequent chronic kidney disease
Project description:Neuropilin-1 (NRP1), a co-receptor for various cytokines, including TGF-β, has been identified as a potential therapeutic target for fibrosis. However, its role and mechanism in renal fibrosis remains elusive. Here, we show that NRP1 is upregulated in distal tubular (DT) cells of patients with transplant renal insufficiency and mice with renal ischemia-reperfusion (I-R) injury. Knockout of Nrp1 reduced multiple endpoints of renal injury and fibrosis. We found that Nrp1 facilitates the binding of TNF-α to its receptor in DT cells after renal injury. This signaling results in a downregulation of lysine crotonylation of the metabolic enzyme Cox4i1, decreased cellular energetics and exacerbation of renal injury. Furthermore, by single-cell RNA-sequencing we found that Nrp1-positive DT cells secrete collagen and communicate with myofibroblasts, exacerbating acute kidney injury (AKI)-induced renal fibrosis by activating Smad3. Dual genetic deletion of Nrp1 and Tgfbr1 in DT cells better improves renal injury and fibrosis than either single knockout. Together, these results reveal that targeting of NRP1 represents a promising strategy for the treatment of AKI and subsequent chronic kidney disease.
Project description:8 week-old male C57BL6J mice were given Gram-negative endotoxin (LPS O111:B4, 10 mg/kg) intraperitoneally at time 0. 18 hrs thereafter, they were administered 10 ml/kg 0.9% saline. Mice were sacrificed at 0, 18, or 42 hrs after LPS challenge. Kidneys were immediately collected into TRIzol for RNA preparation. Renal function was measured on blood collected at the time of tissue harvest At t=0hr, mice had normal baseline renal function. At t=18hr, mice exhibited early renal injury, At t=42hr, mice had either recovered normal renal function or had persistent renal injury. We collected kidneys from 3 mice per time point. For the 42 hr time point, we collected kidneys from 3 mice with recovered renal function and kidneys from 3 mice with persistent renal injury. Mouse kidneys selected at successive stages of renal injury and recovery following systemic LPS challenge and volume resuscitation following LPS challenge.
Project description:Using renal ischemia-reperfusion injury as a model of acute kidney injury, we deteremined temporally-released miRNAs released in urinary exosomes during the injury
Project description:Ischemia-reperfusion injury-induced acute kidney injury is a major cause of chronic kidney disease, lacking effective interventions. We found elevated HNF3α (also known as FOXA1) expression in CKD patients, which correlated with collagen deposition, serum creatinine, and urea levels. Conditional knockout of HNF3α in renal tubular epithelial cells protected against IRI-induced renal fibrosis in vivo. To explore the mechanisms by which HNF3α promotes renal fibrosis, we analyse the genome-wide target sites of HNF3α using CUT&Tag sequencing.