ursodoxicoltaurine and Renal-Insufficiency--Chronic

Inflammatory response and renal fibrosis are the hallmarks of chronic kidney disease (CKD). However, the specific mechanism of aldosterone-induced renal injury in the progress of CKD requires elucidation. Emerging evidence has demonstrated that absent in melanoma 2 (AIM2)-mediated inflammasome activation and endoplasmic reticulum stress (ERS) play a pivotal role in the renal fibrosis. Here, we investigated whether overexpression or deficiency of AIM2 affects ERS and fibrosis in aldosterone-infused renal injury. Interestingly, we found that AIM2 was markedly expressed in the diseased proximal tubules from human and experimental CKD. Mechanically, overactivation of AIM2 aggravated aldosterone-induced ERS and fibrotic changes in vitro while knockdown of AIM2 blunted these effects in vivo and in vitro. By contrast, AIM2 deficiency ameliorated renal structure and function deterioration, decreased proteinuria levels and lowered systolic blood pressure in vivo; silencing of AIM2 blocked inflammasome-mediated signaling pathway, relieved ERS and fibrotic changes in vivo. Furthermore, mineralocorticoid receptor (MR) antagonist eplerenone and ERS inhibitor tauroursodeoxycholic acid (TUDCA) had nephroprotective effects on the basis of AIM2 overactivation in vitro, while they failed to produce a more remarkable renoprotective effect on the treatment of AIM2 silence in vitro. Notably, the combination of TUDCA with AIM2 knockdown significantly reduced proteinuria levels in vivo. Additionally, immunofluorescence assay identified that apoptosis-associated speck-like protein (ASC) recruitment and Gasdermin-D (GSDMD) cleavage respectively occurred in the glomeruli and tubules in vivo. These findings establish a crucial role for AIM2 inflammasome in aldosterone-induced renal injury, which may provide a novel therapeutic target for the pathogenesis of CKD.

Topics: Acute Kidney Injury; Aldosterone; Animals; DNA-Binding Proteins; Endoplasmic Reticulum Stress; Fibrosis; Inflammasomes; Male; Mice, Inbred C57BL; Renal Insufficiency, Chronic; Taurochenodeoxycholic Acid

Chronic kidney disease (CKD) leads to the loss of kidney function, as well as the dysfunction of several other organs due to the release of uremic toxins into the system. In a murine CKD model, reactive oxygen species (ROS) generation and endoplasmic reticulum (ER) stress are increased in the hippocampus. Mesenchymal stem cells (MSCs) are one of the candidates for cell-based therapy for CKD; however severe pathophysiological conditions can decrease their therapeutic potential. To address these issues, we established tauroursodeoxycholic acid (TUDCA)-treated MSCs using MSCs isolated from patients with CKD (CKD-hMSCs) and assessed the survival and ROS generation of neural cell line SH-SY5Y cells by co-culturing with TUDCA-treated CKD-hMSCs. In the presence of the uremic toxin

Topics: Adenine; Animals; Cell Line; Cell Survival; Coculture Techniques; Cresols; Disease Models, Animal; Endoplasmic Reticulum Stress; Hippocampus; Humans; Mesenchymal Stem Cell Transplantation; Mesenchymal Stem Cells; Mice; PrPC Proteins; Reactive Oxygen Species; Renal Insufficiency, Chronic; Signal Transduction; Taurochenodeoxycholic Acid; Up-Regulation

Although autologous human mesenchymal stem cells (hMSCs) are a promising source for regenerative stem cell therapy in chronic kidney disease (CKD), the barriers associated with pathophysiological conditions limit therapeutic applicability to patients. We confirmed that level of cellular prion protein (PrP

Topics: Animals; Biomarkers; Cell Proliferation; Cytokines; Disease Models, Animal; Humans; Inflammation Mediators; Ischemia; Membrane Potential, Mitochondrial; Mesenchymal Stem Cell Transplantation; Mesenchymal Stem Cells; Mice; Mitochondria; Mitophagy; PrPC Proteins; Renal Insufficiency, Chronic; Taurochenodeoxycholic Acid