PMID- 36253507
OWN - NLM
STAT- MEDLINE
DCOM- 20221019
LR  - 20230117
IS  - 1550-7416 (Electronic)
IS  - 1550-7416 (Linking)
VI  - 24
IP  - 6
DP  - 2022 Oct 17
TI  - Identification of Potential Megalin/Cubilin Substrates Using Extensive Proteomics 
      Quantification from Kidney Megalin-Knockdown Mice.
PG  - 109
LID - 10.1208/s12248-022-00758-2 [doi]
AB  - Megalin and cubilin, endocytic proteins present in the proximal tubule of the 
      kidney, are responsible for reabsorbing filtered proteins from urine. Our 
      hypothesis was that potential substrates of megalin/cubilin could be identified 
      by examining urinary protein differences between control (WT) mice and 
      kidney-specific megalin knockdown (KD) mice. Using the IonStar proteomics 
      approach, 877 potential megalin/cubilin substrates were discovered, with 23 of 
      these compounds representing known megalin/cubilin substrates. Some of the 
      proteins with the largest fold changes in the urine between KD and WT included 
      the known megalin substrates retinol-binding protein and vitamin D-binding 
      protein. Of the total proteins identified as novel substrates, about 
      three-quarters of compounds had molecular weights (MWs) below 69 kDa, the MW of 
      albumin, and the remaining had higher MWs, with about 5% of the proteins having 
      MWs greater than 150 kDa. Sex differences in the number of identified substrates 
      occurred, but this may be due to differences in kidney megalin expression between 
      both male and female megalin KD and WT animals, with the ratio of megalin between 
      WT and KD being 2.76 and 2.14 for female and male mice, respectively. The top 
      three ingenuity canonical pathways based on the urinary proteins in both female 
      and male KD mice were acute phase response signaling, liver X receptor/retinoid X 
      receptor activation, and intrinsic prothrombin activation pathways. In 
      conclusion, analysis of urine samples from kidney-specific megalin KD and WT mice 
      was found to be useful for the identification of potential endogenous substrates 
      for megalin and cubilin.
CI  - (c) 2022. The Author(s), under exclusive licence to American Association of 
      Pharmaceutical Scientists.
FAU - Zhao, Bei
AU  - Zhao B
AD  - Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical 
      Sciences, University at Buffalo, State University of New York, Buffalo, NY, 
      14214-8033, USA.
FAU - Tu, Chengjian
AU  - Tu C
AD  - Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical 
      Sciences, University at Buffalo, State University of New York, Buffalo, NY, 
      14214-8033, USA.
AD  - New York State Center of Excellence in Bioinformatics and Life Sciences, 701 
      Ellicott Street, Buffalo, New York, 14203, USA.
FAU - Shen, Shichen
AU  - Shen S
AD  - Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical 
      Sciences, University at Buffalo, State University of New York, Buffalo, NY, 
      14214-8033, USA.
AD  - New York State Center of Excellence in Bioinformatics and Life Sciences, 701 
      Ellicott Street, Buffalo, New York, 14203, USA.
FAU - Qu, Jun
AU  - Qu J
AD  - Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical 
      Sciences, University at Buffalo, State University of New York, Buffalo, NY, 
      14214-8033, USA.
AD  - New York State Center of Excellence in Bioinformatics and Life Sciences, 701 
      Ellicott Street, Buffalo, New York, 14203, USA.
FAU - Morris, Marilyn E
AU  - Morris ME
AD  - Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical 
      Sciences, University at Buffalo, State University of New York, Buffalo, NY, 
      14214-8033, USA. memorris@buffalo.edu.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20221017
PL  - United States
TA  - AAPS J
JT  - The AAPS journal
JID - 101223209
RN  - 0 (Albumins)
RN  - 0 (Liver X Receptors)
RN  - 0 (Low Density Lipoprotein Receptor-Related Protein-2)
RN  - 0 (Receptors, Cell Surface)
RN  - 0 (Retinoid X Receptors)
RN  - 0 (Retinol-Binding Proteins)
RN  - 0 (Vitamin D-Binding Protein)
RN  - 0 (intrinsic factor-cobalamin receptor)
RN  - 9001-26-7 (Prothrombin)
SB  - IM
MH  - Albumins
MH  - Animals
MH  - Endocytosis/physiology
MH  - Female
MH  - Kidney/metabolism
MH  - Kidney Tubules, Proximal/metabolism
MH  - Liver X Receptors/metabolism
MH  - *Low Density Lipoprotein Receptor-Related Protein-2/metabolism
MH  - Male
MH  - Mice
MH  - Proteomics
MH  - Prothrombin/metabolism
MH  - Receptors, Cell Surface
MH  - Retinoid X Receptors/metabolism
MH  - Retinol-Binding Proteins/metabolism
MH  - *Vitamin D-Binding Protein/metabolism
OTO - NOTNLM
OT  - Endogenous proteins
OT  - Kidney reabsorption
OT  - LC-MS/MS
OT  - Megalin/cubilin
OT  - Receptor-mediated endocytosis
EDAT- 2022/10/18 06:00
MHDA- 2022/10/20 06:00
CRDT- 2022/10/17 23:30
PHST- 2022/08/04 00:00 [received]
PHST- 2022/09/26 00:00 [accepted]
PHST- 2022/10/17 23:30 [entrez]
PHST- 2022/10/18 06:00 [pubmed]
PHST- 2022/10/20 06:00 [medline]
AID - 10.1208/s12248-022-00758-2 [pii]
AID - 10.1208/s12248-022-00758-2 [doi]
PST - epublish
SO  - AAPS J. 2022 Oct 17;24(6):109. doi: 10.1208/s12248-022-00758-2.