PMID- 27913625
OWN - NLM
STAT- MEDLINE
DCOM- 20170601
LR  - 20210206
IS  - 1083-351X (Electronic)
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 292
IP  - 2
DP  - 2017 Jan 13
TI  - Absence of miR-146a in Podocytes Increases Risk of Diabetic Glomerulopathy via 
      Up-regulation of ErbB4 and Notch-1.
PG  - 732-747
LID - 10.1074/jbc.M116.753822 [doi]
AB  - Podocyte injury is an early event in diabetic kidney disease and is a hallmark of 
      glomerulopathy. MicroRNA-146a (miR-146a) is highly expressed in many cell types 
      under homeostatic conditions, and plays an important anti-inflammatory role in 
      myeloid cells. However, its role in podocytes is unclear. Here, we show that 
      miR-146a expression levels decrease in the glomeruli of patients with type 2 
      diabetes (T2D), which correlates with increased albuminuria and glomerular 
      damage. miR-146a levels are also significantly reduced in the glomeruli of 
      albuminuric BTBR ob/ob mice, indicating its significant role in maintaining 
      podocyte health. miR-146a-deficient mice (miR-146a(-/-)) showed accelerated 
      development of glomerulopathy and albuminuria upon streptozotocin (STZ)-induced 
      hyperglycemia. The miR-146a targets, Notch-1 and ErbB4, were also significantly 
      up-regulated in the glomeruli of diabetic patients and mice, suggesting induction 
      of the downstream TGFbeta signaling. Treatment with a pan-ErbB kinase inhibitor 
      erlotinib with nanomolar activity against ErbB4 significantly suppressed diabetic 
      glomerular injury and albuminuria in both WT and miR-146a(-/-) animals. Treatment 
      of podocytes in vitro with TGF-beta1 resulted in increased expression of Notch-1, 
      ErbB4, pErbB4, and pEGFR, the heterodimerization partner of ErbB4, suggesting 
      increased ErbB4/EGFR signaling. TGF-beta1 also increased levels of inflammatory 
      cytokine monocyte chemoattractant protein-1 (MCP-1) and MCP-1 induced protein-1 
      (MCPIP1), a suppressor of miR-146a, suggesting an autocrine loop. Inhibition of 
      ErbB4/EGFR with erlotinib co-treatment of podocytes suppressed this signaling. 
      Our findings suggest a novel role for miR-146a in protecting against diabetic 
      glomerulopathy and podocyte injury. They also point to ErbB4/EGFR as a novel, 
      druggable target for therapeutic intervention, especially because several 
      pan-ErbB inhibitors are clinically available.
CI  - (c) 2017 by The American Society for Biochemistry and Molecular Biology, Inc.
FAU - Lee, Ha Won
AU  - Lee HW
AD  - From the Departments of Internal Medicine and.
FAU - Khan, Samia Q
AU  - Khan SQ
AD  - From the Departments of Internal Medicine and.
FAU - Khaliqdina, Shehryar
AU  - Khaliqdina S
AD  - From the Departments of Internal Medicine and.
FAU - Altintas, Mehmet M
AU  - Altintas MM
AD  - From the Departments of Internal Medicine and.
FAU - Grahammer, Florian
AU  - Grahammer F
AD  - the Department of Medicine IV, Medical Center, Faculty of Medicine, University of 
      Freiburg, 79106 Freiburg, Germany.
FAU - Zhao, Jimmy L
AU  - Zhao JL
AD  - the Department of Medicine, New York Presbyterian/Weill Cornell Medical Center, 
      New York, New York 10065.
AD  - the Division of Biology and Biological Engineering, California Institute of 
      Technology, Pasadena, California 91125.
FAU - Koh, Kwi Hye
AU  - Koh KH
AD  - From the Departments of Internal Medicine and.
FAU - Tardi, Nicholas J
AU  - Tardi NJ
AD  - From the Departments of Internal Medicine and.
FAU - Faridi, Mohd Hafeez
AU  - Faridi MH
AD  - From the Departments of Internal Medicine and.
FAU - Geraghty, Terese
AU  - Geraghty T
AD  - From the Departments of Internal Medicine and.
FAU - Cimbaluk, David J
AU  - Cimbaluk DJ
AD  - Pathology, Rush University Medical Center, Chicago, Illinois 60612.
FAU - Susztak, Katalin
AU  - Susztak K
AD  - the Department of Medicine, Renal Electrolyte and Hypertension Division, Perelman 
      School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104.
FAU - Moita, Luis F
AU  - Moita LF
AD  - the Instituto Gulbenkian de Ciencia, Rua da Quinta Grande 6, 2780-156 Oeiras, 
      Portugal.
FAU - Baltimore, David
AU  - Baltimore D
AD  - the Division of Biology and Biological Engineering, California Institute of 
      Technology, Pasadena, California 91125.
FAU - Tharaux, Pierre-Louis
AU  - Tharaux PL
AD  - the Paris Cardiovascular Centre (PARCC), Institut National de la Sante et de la 
      Recherche Medicale (INSERM), 75015 Paris, France and the Universite Paris 
      Descartes, Sorbonne Paris Cite, 75270 Paris, France.
FAU - Huber, Tobias B
AU  - Huber TB
AD  - the Department of Medicine IV, Medical Center, Faculty of Medicine, University of 
      Freiburg, 79106 Freiburg, Germany.
AD  - the BIOSS Center for Biological Signalling Studies, Albert-Ludwigs-University 
      Freiburg, 79104 Freiburg, Germany.
AD  - the FRIAS, Freiburg Institute for Advanced Studies and ZBSA-Center for Systems 
      Biology, Albert-Ludwigs-University, 79104 Freiburg, Germany, and.
FAU - Kretzler, Matthias
AU  - Kretzler M
AD  - the Division of Nephrology, University of Michigan, Ann Arbor, Michigan 48109.
FAU - Bitzer, Markus
AU  - Bitzer M
AD  - the Division of Nephrology, University of Michigan, Ann Arbor, Michigan 48109.
FAU - Reiser, Jochen
AU  - Reiser J
AD  - From the Departments of Internal Medicine and.
FAU - Gupta, Vineet
AU  - Gupta V
AUID- ORCID: 0000-0001-6987-2550
AD  - From the Departments of Internal Medicine and vineet_gupta@rush.edu.
LA  - eng
GR  - R01 DK087635/DK/NIDDK NIH HHS/United States
GR  - R01 HL109582/HL/NHLBI NIH HHS/United States
GR  - R01 DK100449/DK/NIDDK NIH HHS/United States
GR  - R01 DK107984/DK/NIDDK NIH HHS/United States
GR  - P30 DK081943/DK/NIDDK NIH HHS/United States
GR  - R01 DK076077/DK/NIDDK NIH HHS/United States
GR  - R01 DK084195/DK/NIDDK NIH HHS/United States
GR  - R01 DK106512/DK/NIDDK NIH HHS/United States
PT  - Journal Article
DEP - 20161202
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (Ccl2 protein, mouse)
RN  - 0 (Chemokine CCL2)
RN  - 0 (MicroRNAs)
RN  - 0 (Mirn146 microRNA, mouse)
RN  - 0 (Notch1 protein, mouse)
RN  - 0 (Receptor, Notch1)
RN  - 0 (Tgfb1 protein, mouse)
RN  - 0 (Transforming Growth Factor beta1)
RN  - DA87705X9K (Erlotinib Hydrochloride)
RN  - EC 2.7.10.1 (Erbb4 protein, mouse)
RN  - EC 2.7.10.1 (Receptor, ErbB-4)
RN  - EC 3.1.- (Ribonucleases)
RN  - EC 3.1.- (Zc3h12a protein, mouse)
SB  - IM
MH  - Animals
MH  - Chemokine CCL2/genetics/metabolism
MH  - Diabetes Mellitus, Experimental/drug therapy/genetics/*metabolism/pathology
MH  - Diabetic Nephropathies/drug therapy/genetics/*metabolism/pathology
MH  - Erlotinib Hydrochloride/pharmacology
MH  - Mice
MH  - Mice, Knockout
MH  - MicroRNAs/genetics/*metabolism
MH  - Podocytes/*metabolism/pathology
MH  - Receptor, ErbB-4/*biosynthesis/genetics
MH  - Receptor, Notch1/*biosynthesis/genetics
MH  - Ribonucleases/genetics/metabolism
MH  - Risk Factors
MH  - Signal Transduction/drug effects/genetics
MH  - Transforming Growth Factor beta1/genetics/metabolism
MH  - *Up-Regulation
PMC - PMC5241746
OTO - NOTNLM
OT  - Type 1 diabetes
OT  - diabetic glomerulopathy
OT  - diabetic nephropathy
OT  - kidney
OT  - microRNA (miRNA)
OT  - mir-146a
OT  - podocyte
EDAT- 2016/12/04 06:00
MHDA- 2017/06/02 06:00
PMCR- 2018/01/13
CRDT- 2016/12/04 06:00
PHST- 2016/08/16 00:00 [received]
PHST- 2016/12/01 00:00 [revised]
PHST- 2016/12/04 06:00 [pubmed]
PHST- 2017/06/02 06:00 [medline]
PHST- 2016/12/04 06:00 [entrez]
PHST- 2018/01/13 00:00 [pmc-release]
AID - S0021-9258(20)40202-9 [pii]
AID - M116.753822 [pii]
AID - 10.1074/jbc.M116.753822 [doi]
PST - ppublish
SO  - J Biol Chem. 2017 Jan 13;292(2):732-747. doi: 10.1074/jbc.M116.753822. Epub 2016 
      Dec 2.