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BMC Nephrol. 2018 Jul 6;19(1):167. doi: 10.1186/s12882-018-0980-8.

Efficacy of Hydroxy-L-proline (HYP) analogs in the treatment of primary hyperoxaluria in Drosophila Melanogaster.

Yang H1,2, Male M1,2, Li Y3, Wang N1,2, Zhao C1,2, Jin S3, Hu J3, Chen Z1,2, Ye Z1,2, Xu H4,5.

Author information

1
Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095# Jie Fang Avenue, Wuhan, 430030, China.
2
Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
3
College of Life Sciences, Hubei University, Wuhan, China.
4
Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095# Jie Fang Avenue, Wuhan, 430030, China. xuhuawhu@163.com.
5
Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. xuhuawhu@163.com.

Abstract

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 (W118, 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 (F1 generation) of D. Melanogaster which was used to compare the efficacy of Hydroxy-L-proline (HYP) analogs inhibiting CaOx crystal formation with Vitamin B6 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 B6 (IC50 = 0.6 and 1.8% for standard and dietary salt growth medium respectively) compared to N-acetyl-L-Hydroxyproline (IC50 = 0.1% for both standard and dietary salt growth medium) and Baclofen (IC50 = 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 < 0.0008) for the dietary salt growth medium and (P < 0.063) for standard growth medium.

CONCLUSION:

Addition of Hydroxy-L-Proline analogs to growth medium resulted in the reduction of CaOx crystals formation. These analogs show promise as potential inhibitors for oxalate reduction in Primary Hyperoxaluria.

KEYWORDS:

Drosophila Melanogaster; Hydroxy-L-Proline analogs; Primary hyperoxaluria

PMID:
29980178
PMCID:
PMC6035412
DOI:
10.1186/s12882-018-0980-8
[Indexed for MEDLINE]
Free PMC Article

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