Research group of Professor Hui Peng revealed a new mechanism of peritoneal fibrosis in an article published on Science Translational Medicine

Research group of Professor Hui Peng revealed a new mechanism of peritoneal fibrosis in an article published on Science Translational Medicine

   Dr. Hui Peng, professor and chief of the Department of Nephrology, collaborating with Prof. Zhaoyong Hu from Baylor College of Medicine, published a research article entitled "Inhibition of hyperglycolysis in mesothelial cells prevents peritoneal fibrosis" on June 5, 2019 in Science Translational Medicine (IF 16.796, link: https://stm.sciencemag.org/content/11/495/eaav5341). Dr. Meijun Si, Qianqian Wang and Yin Li from the Division of Nephrology are the co-first authors of the paper. The Third Affiliated Hospital of Sun Yat-sen University is the affiliation of all first authors and the first corresponding author. This study elucidated a mechanism of peritoneal fibrosis from a novel perspective of cellular metabolic reprogramming, and successfully inhibited peritoneal fibrosis in a mouse model using a miRNA triad gene therapy. It is an important advance in the field of peritoneal dialysis research over the past 10 years.

   Peritoneal dialysis is a major renal replacement therapy for patients with end-stage renal disease. However, the long-term application of peritoneal dialysis fluid can cause peritoneal fibrosis and functional failure, which is one of the main reasons for the discontinuation of the peritoneal dialysis by the patient. The mechanism and prevention of peritoneal fibrosis have been the intensively studied for nearly 20 years.

   In this study, researchers obtained 96,446 cells from the effluent of peritoneal dialysis patients and performed single-cell transcriptome sequencing. The result indicated that peritoneal mesothelial cells underwent mesothelial to mesenchymal transition (MMT). Notably, there was a significantly enhanced glycolysis during MMT, suggesting that hyperglycolysis involved in peritoneal fibrosis. The researchers then validated this metabolic reprogramming in peritoneal cells using metabolomics and real-time cellular respiratory function tests. To develop a therapeutic approach, they carried out a microRNA microarray analysis in peritoneal tissues from a mouse model of peritoneal fibrosis, and targeted three microRNAs that are involved in both glycolysis and fibrosis. They then developed a triad of AAV1 (adeno-associated viruses type1) - miRNAs to target hyperglycolysis and fibrotic signaling and successfully prevented peritoneal dialysis-induced peritoneal fibrosis.

Figure 1.. a-b t-SNE of cells from the effluent of peritoneal dialysis patients; c Trajectory analysis of MMT in mesothelial cells.

 Dr. Hui Peng’s research group has focused on both energy metabolism abnormalities and organ fibrosis in recent years. The team published an article in Nature Communications in 2017, revealing that exercise can improve renal tubular energy metabolism and alleviate kidney damage through myokines. The latest research article on peritoneal dialysis provides an insight into the pathological mechanism of peritoneal fibrosis and theoretical basis for the clinical application of AAV-based gene therapy.

Figure 2. a. Representative images showing excessive fragmented mitochondria in peritoneal mesothelial cells in response to PD fluid in PhaMexcised mice. b. Masson’s trichrome staining of peritoneal tissue showing AAV1-miRNA triad prevented both visceral and parietal peritoneal fibrosis.

   This research was supported by the National Natural Science Foundation of China, the Natural Science Foundation of Guangdong Province, and the Science and Technology Program of Guangzhou. The first author, Meijun Si, was funded by the “Qingmiao Program” in our hospital. This study proves that in recent years, our hospital has achieved remarkable results in improving the education and training of employee’s research. The Division of Nephrology has made great efforts to improve both research and clinical quality.