PMID- 24523358
OWN - NLM
STAT- MEDLINE
DCOM- 20141028
LR  - 20211021
IS  - 1460-2385 (Electronic)
IS  - 0931-0509 (Print)
IS  - 0931-0509 (Linking)
VI  - 29
IP  - 4
DP  - 2014 Apr
TI  - Keap1 inhibition attenuates glomerulosclerosis.
PG  - 783-91
LID - 10.1093/ndt/gfu002 [doi]
AB  - BACKGROUND: NFE2-related factor 2 (Nrf2) is a master regulatory transcription 
      factor for antioxidant genes. Inhibition of its adaptor protein, Kelch-like 
      ECH-associated protein 1 (Keap1), activates Nrf2. Podocyte injury triggers the 
      progressive deterioration of glomerular damage toward glomerulosclerosis. We 
      examined whether modulation of the Keap1-Nrf2 system has an impact on this 
      process. METHODS: Nrf2 null-mutant (KO) and Keap1 hypomorphic knockdown (KD) mice 
      were crossed with NEP25 mice, in which podocyte-specific injury can be induced by 
      an immunotoxin. RESULTS: Thiobarbituric acid reactive substances, 
      8-hydroxydeoxyguanosine and phosphorylated JNK were increased in the injured 
      NEP25 kidney. Real-time PCR revealed that Keap1 KD upregulated Nrf2 target genes, 
      including Gclc, Gclm, Gstp1, Gstp2 and Nqo1 in the glomerulus. However, podocyte 
      injury did not upregulate these genes in Keap1 wild-type mice, nor did it further 
      increase the expression of those genes in Keap1 KD mice. Three weeks after the 
      induction of podocyte injury, glomerulosclerosis was considerably more attenuated 
      in Keap1 KD mice than in control mice (median sclerosis index, 0.27 versus 3.03, 
      on a 0-4 scale). Keap1 KD mice also showed considerably preserved nephrin 
      staining (median index, 6.76 versus 0.91, on a 0-8 scale) and decreased glomeruli 
      containing desmin-positive injured podocytes (median percentage, 24.5% versus 
      85.8%), along with a decrease in mRNAs for Fn1, Tgfb1, Col4a4 and Col1a2. 
      CONCLUSIONS: Thus, podocyte injury cannot effectively activate Nrf2, but Nrf2 
      activation by Keap1 knockdown attenuates glomerulosclerosis. These results 
      indicate that the Nrf2-Keap1 system is a promising drug target for the treatment 
      of chronic kidney diseases.
FAU - Miyazaki, Yoichi
AU  - Miyazaki Y
AD  - Division of Kidney and Hypertension, Department of Internal Medicine, Jikei 
      University School of Medicine, Tokyo, Japan.
FAU - Shimizu, Akihiro
AU  - Shimizu A
FAU - Pastan, Ira
AU  - Pastan I
FAU - Taguchi, Keiko
AU  - Taguchi K
FAU - Naganuma, Eriko
AU  - Naganuma E
FAU - Suzuki, Takafumi
AU  - Suzuki T
FAU - Hosoya, Tatsuo
AU  - Hosoya T
FAU - Yokoo, Takashi
AU  - Yokoo T
FAU - Saito, Akihiko
AU  - Saito A
FAU - Miyata, Toshio
AU  - Miyata T
FAU - Yamamoto, Masayuki
AU  - Yamamoto M
FAU - Matsusaka, Taiji
AU  - Matsusaka T
LA  - eng
GR  - Intramural NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Intramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20140211
PL  - England
TA  - Nephrol Dial Transplant
JT  - Nephrology, dialysis, transplantation : official publication of the European 
      Dialysis and Transplant Association - European Renal Association
JID - 8706402
RN  - 0 (Adaptor Proteins, Signal Transducing)
RN  - 0 (Antibodies, Monoclonal)
RN  - 0 (Antioxidants)
RN  - 0 (B3(Fv)-PE38KDEL recombinant immunotoxin)
RN  - 0 (Cytoskeletal Proteins)
RN  - 0 (Exotoxins)
RN  - 0 (Immunotoxins)
RN  - 0 (Keap1 protein, mouse)
RN  - 0 (Kelch-Like ECH-Associated Protein 1)
RN  - 0 (NF-E2-Related Factor 2)
RN  - 9007-49-2 (DNA)
SB  - IM
MH  - Adaptor Proteins, Signal Transducing/antagonists & 
      inhibitors/biosynthesis/*genetics
MH  - Alleles
MH  - Animals
MH  - Antibodies, Monoclonal/*toxicity
MH  - Antioxidants/pharmacology
MH  - Cytoskeletal Proteins/antagonists & inhibitors/biosynthesis/*genetics
MH  - DNA/*genetics
MH  - Disease Models, Animal
MH  - Exotoxins/toxicity
MH  - Female
MH  - *Gene Expression Regulation
MH  - Glomerulosclerosis, Focal Segmental/*genetics/metabolism/pathology
MH  - Immunotoxins
MH  - Kelch-Like ECH-Associated Protein 1
MH  - Kidney Glomerulus/drug effects/metabolism/pathology
MH  - Male
MH  - Mice
MH  - Mice, Mutant Strains
MH  - NF-E2-Related Factor 2/biosynthesis/*genetics
MH  - Oxidative Stress/drug effects/*genetics
MH  - Podocytes/drug effects/metabolism/pathology
MH  - Real-Time Polymerase Chain Reaction
PMC - PMC3967835
OTO - NOTNLM
OT  - antioxidant genes
OT  - glomerulosclerosis
OT  - hypomorphic allele
OT  - oxidative stress
EDAT- 2014/02/14 06:00
MHDA- 2014/10/29 06:00
PMCR- 2015/04/01
CRDT- 2014/02/14 06:00
PHST- 2014/02/14 06:00 [entrez]
PHST- 2014/02/14 06:00 [pubmed]
PHST- 2014/10/29 06:00 [medline]
PHST- 2015/04/01 00:00 [pmc-release]
AID - gfu002 [pii]
AID - 10.1093/ndt/gfu002 [doi]
PST - ppublish
SO  - Nephrol Dial Transplant. 2014 Apr;29(4):783-91. doi: 10.1093/ndt/gfu002. Epub 
      2014 Feb 11.