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2018 ; 19
(1
): 167
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Efficacy of Hydroxy-L-proline (HYP) analogs in the treatment of primary
hyperoxaluria in Drosophila Melanogaster
#MMPMID29980178
Yang H
; Male M
; Li Y
; Wang N
; Zhao C
; Jin S
; Hu J
; Chen Z
; Ye Z
; Xu H
BMC Nephrol
2018[Jul]; 19
(1
): 167
PMID29980178
show ga
BACKGROUND: Substrate reduction therapy with analogs reduces the accumulation of
substrates by inhibiting the metabolic pathways involved in their biosynthesis,
providing new treatment options for patients with primary hyperoxalurias (PHs)
that often progress to end-stage renal disease (ESRD). This research aims to
evaluate the inhibition efficacy of Hydroxy-L-proline (HYP) analogs against
calcium oxalate (CaOx) crystal formation in the Drosophila Melanogaster (D.
Melanogaster) by comparing them with Pyridoxine (Vitamin B6). METHODS: Three
stocks of Drosophila Melanogaster (W(118), CG3926 RNAi, and Act5C-GAL4/CyO) were
utilized. Two stocks (CG3926 RNAi and Act5C-GAL4 /CyO) were crossed to generate
the Act5C?>?dAGXT RNAi recombinant line (F(1) generation) of D. Melanogaster
which was used to compare the efficacy of Hydroxy-L-proline (HYP) analogs
inhibiting CaOx crystal formation with Vitamin B(6) as the traditional therapy
for primary hyperoxaluria. RESULTS: Nephrolithiasis model was successfully
constructed by downregulating the function of the dAGXT gene in D. Melanogaster
(P-Value?=?0.0045). Furthermore, the efficacy of Hydroxy-L-proline (HYP) analogs
against CaOx crystal formation was demonstrated in vivo using D. Melanogaster
model; the results showed that these L-Proline analogs were better in inhibiting
stone formation at very low concentrations than Vitamin B(6) (IC(50)?=?0.6 and
1.8% for standard and dietary salt growth medium respectively) compared to
N-acetyl-L-Hydroxyproline (IC(50)?=?0.1% for both standard and dietary salt
growth medium) and Baclofen (IC(50)?=?0.06 and 0.1% for standard and dietary salt
growth medium respectively). Analysis of variance (ANOVA) also showed that
Hydroxy-L-proline (HYP) analogs were better alternatives for CaOx inhibition at
very low concentration especially when both genetics and environmental factors
are intertwined (p?
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