Dyslipidemia Aggravates Oxalate Sodium Cystal Induced Kidney Injury: A Multiple-Omics Research

Objective: Previous study found that high incidence of dyslipidemia in urolithiasis patients and transgenetic mice with higher serum lipid would aggravate the calcium oxalate induced kidney injury.To make a comprehensive research about the effect of dyslipidemia on calcium oxalate induced kidney injury,clinical samples,animal model,cultured cell line were collected to conducted genomics,proteomics and metabolmics.Methods: One.There are eight SNP variants of LDLR genes were analysed by snapwshot technique in 360 cases and 336 control;Two: comparative proteomics analysis was conducted in renal tissue from ApoE KO and WT mice by iTRAQ platform.Three: The cytotoxicity of ox-LDL only,sodium oxalate only and combination of ox-LDL and sodium oxalate on HK cells were detected by western blotting.Four: The metabolic distortions of cytotoxicity from ox-LDL only,sodium oxalate only and combination of ox-LDL and sodium oxalate on HK cells were detected by UHPLC-Q-TOF/MS.Results: One: There were significant difference of SNP variant rs1003723OR0.71(0.51,0.98)? rs2738464 OR1.67(1.23,2.26)? rs1433099 OR1.38(1.02,1.86)between kidney stone cases and control.The data indicated that the mutation of rs1003723 might play a protective role in the pathogenesis of kidney stone,while the mutation of rest two sites would be susceptible for urolithiasis.Two: Based on the date from comparative proteomics,there were 225 and 204 different proteins in wild type mice and ApoE KO mice,respectively.According to the KEGG PATHWAY Database,glycolysis /gluconeogenesis,Pyruvate metabolis,glyoxylate and dicarboxylate metabolism were dysfunctional in the ApoE KO mice.Meanwhile netrin-4 and HNF-1?,which mediated the pro-fibrosis process,might participated the aggravation of crystal induced kidney injury from ApoE KO.Three: under the co-stimulation of ox-LDL and sodium oxalate,Bax?PARP and cytochrome c were up-regulated and IKK?/? was activatied,as well as phosphorylation of I?B? and NF-?B.The mTOR/AKT,MAPK ?STAT3 and PKC P53 pathway were also activated by the synergistic reaction.Four: energy metabolism,phospholipid metabolism,amino acid metabolism of tryptophan and valine,as well as oxidative stress related molecule participated the metabolic perturbation by ox-LDL and sodium oxlate in HK-2 cell line.Conclusion: There was association between LDLR SNP variants and kidney stone formation.Netrin-4 and HNF-1? involved the accelerational process of crystal induced kidney injury by ApoE KO.Many signal pathway were activated and many metabolic pathway were dysfunctional under the co-exist of ox-LDL and sodium oxalate.