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2014 ; 29
(4
): 783-91
Nephropedia Template TP
Miyazaki Y
; Shimizu A
; Pastan I
; Taguchi K
; Naganuma E
; Suzuki T
; Hosoya T
; Yokoo T
; Saito A
; Miyata T
; Yamamoto M
; Matsusaka T
Nephrol Dial Transplant
2014[Apr]; 29
(4
): 783-91
PMID24523358
show ga
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.
|*Gene Expression Regulation
[MESH]
|Adaptor Proteins, Signal Transducing/antagonists &
inhibitors/biosynthesis/*genetics
[MESH]
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