PMID- 29330340 OWN - NLM STAT- MEDLINE DCOM- 20190916 LR - 20220408 IS - 1533-3450 (Electronic) IS - 1046-6673 (Print) IS - 1046-6673 (Linking) VI - 29 IP - 4 DP - 2018 Apr TI - The Adiponectin Receptor Agonist AdipoRon Ameliorates Diabetic Nephropathy in a Model of Type 2 Diabetes. PG - 1108-1127 LID - 10.1681/ASN.2017060627 [doi] AB - Adiponectin exerts renoprotective effects against diabetic nephropathy (DN) by activating the AMP-activated protein kinase (AMPK)/peroxisome proliferative-activated receptor-alpha (PPARalpha) pathway through adiponectin receptors (AdipoRs). AdipoRon is an orally active synthetic adiponectin receptor agonist. We investigated the expression of AdipoRs and the associated intracellular pathways in 27 patients with type 2 diabetes and examined the effects of AdipoRon on DN development in male C57BLKS/J db/db mice, glomerular endothelial cells (GECs), and podocytes. The extent of glomerulosclerosis and tubulointerstitial fibrosis correlated with renal function deterioration in human kidneys. Expression of AdipoR1, AdipoR2, and Ca(2+)/calmodulin-dependent protein kinase kinase-beta (CaMKKbeta) and numbers of phosphorylated liver kinase B1 (LKB1)- and AMPK-positive cells significantly decreased in the glomeruli of early stage human DN. AdipoRon treatment restored diabetes-induced renal alterations in db/db mice. AdipoRon exerted renoprotective effects by directly activating intrarenal AdipoR1 and AdipoR2, which increased CaMKKbeta, phosphorylated Ser(431)LKB1, phosphorylated Thr(172)AMPK, and PPARalpha expression independently of the systemic effects of adiponectin. AdipoRon-induced improvement in diabetes-induced oxidative stress and inhibition of apoptosis in the kidneys ameliorated relevant intracellular pathways associated with lipid accumulation and endothelial dysfunction. In high-glucose-treated human GECs and murine podocytes, AdipoRon increased intracellular Ca(2+) levels that activated a CaMKKbeta/phosphorylated Ser(431)LKB1/phosphorylated Thr(172)AMPK/PPARalpha pathway and downstream signaling, thus decreasing high-glucose-induced oxidative stress and apoptosis and improving endothelial dysfunction. AdipoRon further produced cardioprotective effects through the same pathway demonstrated in the kidney. Our results show that AdipoRon ameliorates GEC and podocyte injury by activating the intracellular Ca(2+)/LKB1-AMPK/PPARalpha pathway, suggesting its efficacy for treating type 2 diabetes-associated DN. CI - Copyright (c) 2018 by the American Society of Nephrology. FAU - Kim, Yaeni AU - Kim Y AD - Division of Nephrology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea. AD - Division of Nephrology, Department of Internal Medicine, Incheon St. Mary's Hospital, Incheon, Korea. FAU - Lim, Ji Hee AU - Lim JH AD - Division of Nephrology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea. AD - Division of Nephrology, Department of Internal Medicine, Institute for Aging and Metabolic Diseases, Seoul St. Mary's Hospital, Seoul, Korea; and. FAU - Kim, Min Young AU - Kim MY AD - Division of Nephrology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea. AD - Division of Nephrology, Department of Internal Medicine, Institute for Aging and Metabolic Diseases, Seoul St. Mary's Hospital, Seoul, Korea; and. FAU - Kim, Eun Nim AU - Kim EN AD - Division of Nephrology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea. AD - Division of Nephrology, Department of Internal Medicine, Institute for Aging and Metabolic Diseases, Seoul St. Mary's Hospital, Seoul, Korea; and. FAU - Yoon, Hye Eun AU - Yoon HE AD - Division of Nephrology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea. AD - Division of Nephrology, Department of Internal Medicine, Incheon St. Mary's Hospital, Incheon, Korea. FAU - Shin, Seok Joon AU - Shin SJ AD - Division of Nephrology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea. AD - Division of Nephrology, Department of Internal Medicine, Incheon St. Mary's Hospital, Incheon, Korea. FAU - Choi, Bum Soon AU - Choi BS AD - Division of Nephrology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea. AD - Division of Nephrology, Department of Internal Medicine, Institute for Aging and Metabolic Diseases, Seoul St. Mary's Hospital, Seoul, Korea; and. FAU - Kim, Yong-Soo AU - Kim YS AD - Division of Nephrology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea. AD - Division of Nephrology, Department of Internal Medicine, Institute for Aging and Metabolic Diseases, Seoul St. Mary's Hospital, Seoul, Korea; and. FAU - Chang, Yoon Sik AU - Chang YS AD - Division of Nephrology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea. AD - Division of Nephrology, Department of Internal Medicine, Yeouido St. Mary's Hospital, Seoul, Korea. FAU - Park, Cheol Whee AU - Park CW AD - Division of Nephrology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea; cheolwhee@hanmail.net. AD - Division of Nephrology, Department of Internal Medicine, Institute for Aging and Metabolic Diseases, Seoul St. Mary's Hospital, Seoul, Korea; and. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20180112 PL - United States TA - J Am Soc Nephrol JT - Journal of the American Society of Nephrology : JASN JID - 9013836 RN - 0 (ADIPOR1 protein, human) RN - 0 (ADIPOR2 protein, human) RN - 0 (AdipoRon) RN - 0 (Adiponectin) RN - 0 (PPAR alpha) RN - 0 (Piperidines) RN - 0 (Receptors, Adiponectin) RN - 0 (Receptors, Leptin) RN - 0 (adiponectin receptor 1, mouse) RN - 0 (adiponectin receptor 2, mouse) RN - 0 (leptin receptor, mouse) RN - EC 2.7.11.1 (Protein Serine-Threonine Kinases) RN - EC 2.7.11.1 (Stk11 protein, mouse) RN - EC 2.7.11.17 (Calcium-Calmodulin-Dependent Protein Kinase Kinase) RN - EC 2.7.11.31 (AMP-Activated Protein Kinases) RN - IY9XDZ35W2 (Glucose) SB - IM MH - AMP-Activated Protein Kinases/physiology MH - Adiponectin/*physiology MH - Animals MH - Apoptosis/drug effects MH - Calcium-Calmodulin-Dependent Protein Kinase Kinase/metabolism MH - Cells, Cultured MH - Diabetes Mellitus, Type 2/*complications MH - Diabetic Nephropathies/*drug therapy/metabolism/prevention & control MH - Endothelial Cells/drug effects/metabolism MH - Glucose/pharmacology MH - Humans MH - Male MH - Mice MH - Mice, Inbred C57BL MH - Mice, Obese MH - Oxidative Stress/drug effects MH - PPAR alpha/physiology MH - Phosphorylation MH - Piperidines/pharmacology/*therapeutic use MH - Podocytes/drug effects MH - Protein Processing, Post-Translational MH - Protein Serine-Threonine Kinases/physiology MH - Receptors, Adiponectin/*agonists/*analysis/physiology MH - Receptors, Leptin/deficiency PMC - PMC5875945 OTO - NOTNLM OT - AdipoRon OT - Lipotoxicity OT - diabetic nephropathy OT - oxidative stress EDAT- 2018/01/14 06:00 MHDA- 2019/09/17 06:00 PMCR- 2019/04/01 CRDT- 2018/01/14 06:00 PHST- 2017/06/08 00:00 [received] PHST- 2017/12/07 00:00 [accepted] PHST- 2018/01/14 06:00 [pubmed] PHST- 2019/09/17 06:00 [medline] PHST- 2018/01/14 06:00 [entrez] PHST- 2019/04/01 00:00 [pmc-release] AID - ASN.2017060627 [pii] AID - 2017060627 [pii] AID - 10.1681/ASN.2017060627 [doi] PST - ppublish SO - J Am Soc Nephrol. 2018 Apr;29(4):1108-1127. doi: 10.1681/ASN.2017060627. Epub 2018 Jan 12.