PMID- 36682034 OWN - NLM STAT- MEDLINE DCOM- 20230427 LR - 20230502 IS - 1549-4918 (Electronic) IS - 1066-5099 (Linking) VI - 41 IP - 4 DP - 2023 Apr 25 TI - Mesenchymal Stem Cell-Derived Exosomes Ameliorate Diabetic Kidney Disease Through the NLRP3 Signaling Pathway. PG - 368-383 LID - 10.1093/stmcls/sxad010 [doi] AB - Diabetic kidney disease (DKD) is the leading cause of end-stage renal disease worldwide. Exosomes (Exo) derived from human umbilical cord mesenchymal stem cells (HUC-MSCs) have been demonstrated to be an effective therapy for DKD, but the underlying mechanisms of this action remain poorly defined. We investigated the association of DKD with inflammasome activation and the pathophysiological relevance of Exo-mediated inflammation relief as well as damage repair in this progression. We co-cultured podocytes and HUC-MSCs derived Exo (MSCs-Exo) under high glucose (HG) and injected MSCs-Exo into diabetic mice, then we detected the NLRP3 inflammasome both in vitro and in vivo. We found that HG reduced the viability of podocytes, activated the NLRP3 signaling pathway and increased inflammation in podocytes and diabetic mice. MSCs-Exo attenuated the inflammation, including the expression of IL-6, IL-1beta, IL-18, TNF-alpha; depressed the activation of NLRP3 signaling pathway in podocytes under HG and diabetic mice, ameliorated kidney injury. Furthermore, miR-22-3p, which is relatively highly expressed miRNAs in exosomes of MSCs, may be the key point in this progress, by suppressing the expression of its known target, NLRP3. Knocking down miR-22-3p from MSCs-Exo abolished their anti-inflammation activity and beneficial function both in vitro and in vivo. Collectively, our results have demonstrated that exosomes transferring miR-22-3p protected the podocytes and diabetic mice from inflammation by mediating NLRP3 inflammasome, indicating that MSC-derived exosomes may be a promising therapeutic cell-free strategy for DKD. CI - (c) The Author(s) 2023. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com. FAU - Wang, Yinghui AU - Wang Y AD - Department of Nephrology Research Institute, The Second Hospital of Shandong University, Jinan, Shandong, People's Republic of China. AD - Department of Key Laboratory of Reproductive Endocrinology of Ministry of Education, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, People's Republic of China. FAU - Liu, Jiaxi AU - Liu J AD - Graduate School of Arts and Sciences, Columbia University, New York, USA. FAU - Wang, Honggang AU - Wang H AD - Department of Nephrology Research Institute, The Second Hospital of Shandong University, Jinan, Shandong, People's Republic of China. AD - Department of Key Laboratory of Reproductive Endocrinology of Ministry of Education, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, People's Republic of China. FAU - Lv, Shasha AU - Lv S AD - Department of Nephrology Research Institute, The Second Hospital of Shandong University, Jinan, Shandong, People's Republic of China. AD - Department of Key Laboratory of Reproductive Endocrinology of Ministry of Education, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, People's Republic of China. FAU - Liu, Qingzhen AU - Liu Q AD - Department of Nephrology Research Institute, The Second Hospital of Shandong University, Jinan, Shandong, People's Republic of China. AD - Department of Key Laboratory of Reproductive Endocrinology of Ministry of Education, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, People's Republic of China. FAU - Li, Shan AU - Li S AD - Department of Nephrology Research Institute, The Second Hospital of Shandong University, Jinan, Shandong, People's Republic of China. AD - Department of Key Laboratory of Reproductive Endocrinology of Ministry of Education, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, People's Republic of China. FAU - Yang, Xue AU - Yang X AD - Department of Nephrology Research Institute, The Second Hospital of Shandong University, Jinan, Shandong, People's Republic of China. AD - Department of Key Laboratory of Reproductive Endocrinology of Ministry of Education, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, People's Republic of China. FAU - Liu, Gang AU - Liu G AUID- ORCID: 0000-0002-4664-5459 AD - Department of Nephrology Research Institute, The Second Hospital of Shandong University, Jinan, Shandong, People's Republic of China. AD - Department of Key Laboratory of Reproductive Endocrinology of Ministry of Education, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, People's Republic of China. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't PL - England TA - Stem Cells JT - Stem cells (Dayton, Ohio) JID - 9304532 RN - 0 (Inflammasomes) RN - 0 (NLR Family, Pyrin Domain-Containing 3 Protein) RN - 0 (MicroRNAs) RN - 0 (Nlrp3 protein, mouse) SB - IM MH - Mice MH - Humans MH - Animals MH - Inflammasomes/metabolism MH - NLR Family, Pyrin Domain-Containing 3 Protein/metabolism MH - *Diabetes Mellitus, Experimental/therapy MH - *Diabetic Nephropathies/therapy MH - *Exosomes/metabolism MH - Signal Transduction MH - *MicroRNAs/genetics/metabolism MH - Inflammation/metabolism MH - *Mesenchymal Stem Cells/metabolism OTO - NOTNLM OT - NLRP3 OT - diabetic kidney disease OT - exosomes OT - inflammation OT - mesenchymal stem cells OT - microRNA EDAT- 2023/01/23 06:00 MHDA- 2023/04/27 06:42 CRDT- 2023/01/22 14:06 PHST- 2022/09/16 00:00 [received] PHST- 2023/01/13 00:00 [accepted] PHST- 2023/04/27 06:42 [medline] PHST- 2023/01/23 06:00 [pubmed] PHST- 2023/01/22 14:06 [entrez] AID - 6995438 [pii] AID - 10.1093/stmcls/sxad010 [doi] PST - ppublish SO - Stem Cells. 2023 Apr 25;41(4):368-383. doi: 10.1093/stmcls/sxad010.