PMID- 29717938
OWN - NLM
STAT- MEDLINE
DCOM- 20190708
LR  - 20211204
IS  - 1522-1466 (Electronic)
IS  - 1931-857X (Print)
IS  - 1522-1466 (Linking)
VI  - 315
IP  - 2
DP  - 2018 Aug 1
TI  - Comparison of folate-conjugated rapamycin versus unconjugated rapamycin in an 
      orthologous mouse model of polycystic kidney disease.
PG  - F395-F405
LID - 10.1152/ajprenal.00057.2018 [doi]
AB  - Autosomal-dominant polycystic kidney disease (ADPKD) is a very common genetic 
      disease leading to renal failure. Numerous aberrantly regulated signaling 
      pathways have been identified as promising molecular drug targets for ADPKD 
      therapy. In rodent models, many small-molecule drugs against such targets have 
      proven effective in reducing renal cyst growth. For example, mammalian target of 
      rapamycin (mTOR) inhibition with rapamycin greatly ameliorates renal cystic 
      disease in several rodent models. However, clinical trials with mTOR inhibitors 
      were disappointing largely due to the intolerable extrarenal side effects during 
      long-term treatment with these drugs. Most other potential drug targets in ADPKD 
      are also widely expressed in extrarenal tissues, which makes it likely that 
      untargeted therapies with small-molecule inhibitors against such targets will 
      lead to systemic adverse effects during the necessary long-term treatment of 
      years and decades in ADPKD patients. To overcome this problem, we previously 
      demonstrated that folate-conjugated rapamycin (FC-rapa) targets polycystic 
      kidneys due to the high expression of the folate receptor (FRalpha) and that 
      treatment of a nonortholgous PKD mouse model leads to inhibition of renal cyst 
      growth. Here we show, in a head-to-head comparison with unconjugated rapamycin, 
      that FCrapa inhibits renal cyst growth, mTOR activation, cell cycling, and 
      fibrosis in an orthologous Pkd1 mouse model. Both unconjugated rapamycin and 
      FC-rapa are similarly effective on polycystic kidneys in this model. However, 
      FC-rapa lacks the extrarenal effects of unconjugated rapamycin, in particular 
      immunosuppressive effects. We conclude that folate-conjugation is a promising 
      avenue for increasing the tissue specificity of small-molecule compounds to 
      facilitate very long-term treatment in ADPKD.
FAU - Kipp, Kevin R
AU  - Kipp KR
AD  - Department of Molecular, Cellular, and Developmental Biology; and Neuroscience 
      Research Institute, University of California , Santa Barbara, California.
FAU - Kruger, Samantha L
AU  - Kruger SL
AD  - Department of Molecular, Cellular, and Developmental Biology; and Neuroscience 
      Research Institute, University of California , Santa Barbara, California.
FAU - Schimmel, Margaret F
AU  - Schimmel MF
AD  - Department of Molecular, Cellular, and Developmental Biology; and Neuroscience 
      Research Institute, University of California , Santa Barbara, California.
FAU - Parker, Nikki
AU  - Parker N
AD  - Endocyte, West Lafayette, Indiana.
FAU - Shillingford, Jonathan M
AU  - Shillingford JM
AD  - Endocyte, West Lafayette, Indiana.
FAU - Leamon, Christopher P
AU  - Leamon CP
AD  - Endocyte, West Lafayette, Indiana.
FAU - Weimbs, Thomas
AU  - Weimbs T
AUID- ORCID: 0000-0001-9423-5561
AD  - Department of Molecular, Cellular, and Developmental Biology; and Neuroscience 
      Research Institute, University of California , Santa Barbara, California.
LA  - eng
GR  - R01 DK109563/DK/NIDDK NIH HHS/United States
GR  - R01 DK078043/DK/NIDDK NIH HHS/United States
PT  - Comparative Study
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, Non-P.H.S.
DEP - 20180502
PL  - United States
TA  - Am J Physiol Renal Physiol
JT  - American journal of physiology. Renal physiology
JID - 100901990
RN  - 0 (Folate Receptor 1)
RN  - 0 (Folr1 protein, mouse)
RN  - 0 (Protein Kinase Inhibitors)
RN  - 0 (TRPP Cation Channels)
RN  - 0 (polycystic kidney disease 1 protein)
RN  - 935E97BOY8 (Folic Acid)
RN  - EC 2.7.1.1 (mTOR protein, mouse)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 2.7.7.- (Cre recombinase)
RN  - EC 2.7.7.- (Integrases)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
CIN - Am J Physiol Renal Physiol. 2018 Sep 1;315(3):F535-F536. PMID: 29846111
MH  - A549 Cells
MH  - Animals
MH  - Disease Models, Animal
MH  - Drug Compounding
MH  - Folate Receptor 1/metabolism
MH  - Folic Acid/analogs & derivatives/metabolism/*pharmacology
MH  - Humans
MH  - Integrases/genetics
MH  - Kidney/*drug effects/enzymology
MH  - Mice, Knockout
MH  - Polycystic Kidney, Autosomal Dominant/enzymology/genetics/*prevention & control
MH  - Protein Kinase Inhibitors/metabolism/*pharmacology
MH  - Signal Transduction/drug effects
MH  - Sirolimus/analogs & derivatives/metabolism/*pharmacology
MH  - TOR Serine-Threonine Kinases/*antagonists & inhibitors/metabolism
MH  - TRPP Cation Channels/deficiency/genetics
MH  - Tissue Distribution
PMC - PMC6139519
EDAT- 2018/05/03 06:00
MHDA- 2019/07/10 06:00
PMCR- 2019/08/01
CRDT- 2018/05/03 06:00
PHST- 2018/05/03 06:00 [pubmed]
PHST- 2019/07/10 06:00 [medline]
PHST- 2018/05/03 06:00 [entrez]
PHST- 2019/08/01 00:00 [pmc-release]
AID - F-00057-2018 [pii]
AID - 10.1152/ajprenal.00057.2018 [doi]
PST - ppublish
SO  - Am J Physiol Renal Physiol. 2018 Aug 1;315(2):F395-F405. doi: 
      10.1152/ajprenal.00057.2018. Epub 2018 May 2.