title: Paraoxonase 1 deficiency and hyperhomocysteinemia alter the expression of mouse kidney proteins involved in renal disease.
abstract: METHODS
  Hyperhomocysteinemia (HHcy) is associated with kidney disease and leads to atherosclerosis and thrombosis. Paraoxonase 1 (Pon1), a hydrolase that participates in homocysteine (Hcy) metabolism and is carried in the circulation on high-density lipoprotein, has also been linked to kidney disease and atherothrombosis. Pon1-knockout mice are susceptible to atherosclerosis and exhibit a kidney-associated phenotype, polyuria or urine dilution. We hypothesize that HHcy and Pon1 deficiency are toxic to kidney function because they impair metabolic pathways important for normal kidney homeostasis.
  
  
  RESULTS
  We examined changes in the mouse kidney proteome induced by Pon1 gene deletion and dietary HHcy, using 2D IEF/SDS-PAGE gel electrophoresis and MALDI-TOF mass spectrometry. We found that the expression of ten mouse kidney proteins was altered by the Pon1(-/-) genotype or HHcy. Proteins involved in metabolism of lipid (ApoA-I), protein (Hspd1), carbohydrate (Pdhb, Fbp1-isoform2, Eno1), and energy (Ndufs8, Ldhd) were down-regulated. Proteins involved in lipid transport (Pebp1), oxidative stress response (Prdx2), and cellular detoxification (Glo1) were up-regulated. The kidney proteins altered by HHcy or Pon1 are also altered in renal disease.
  
  
  CONCLUSIONS
  Our findings suggest that excess Hcy is toxic because it deregulates the expression of proteins involved in diverse cellular processes-from lipid, protein, carbohydrate, and energy metabolisms to detoxification and antioxidant defenses-that are essential for normal kidney homeostasis. Dysregulation of these processes can account for the involvement of HHcy and reduced Pon1 in kidney disease. Our findings also show that Pon1 plays an important role in maintaining normal kidney homeostasis.
authors: Institute of Bioorganic Chemistry, Poznań, Poland.
authors: Joanna
authors: J
authors: Suszyńska-Zajczyk
authors: Institute of Bioorganic Chemistry, Poznań, Poland.
authors: Marta
authors: M
authors: Sikora
authors: Institute of Bioorganic Chemistry, Poznań, Poland; Department of Biochemistry and Biotechnology, University of Life Sciences, Poznań, Poland; Department of Microbiology & Molecular Genetics, Rutgers-New Jersey Medical School, International Center for Public Health, Newark, NJ, USA. Electronic address: jakubows@njms.rutgers.edu.
authors: Hieronim
authors: H
authors: Jakubowski
mesh_terms: D000818:Animals; D043303:Aryldialkylphosphatase / Q000172:deficiency* / Q000235:genetics; D015870:Gene Expression; D020138:Hyperhomocysteinemia / Q000378:metabolism*; D007668:Kidney / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D020543:Proteome / Q000378:metabolism
chemical_list: D020543:Proteome; D043303:Aryldialkylphosphatase; C560867:PON1 protein, mouse
keywords: High-methionine diet; Hyperhomocysteinemia; Kidney disease; Mouse kidney proteome; Paraoxonase 1; Polyuria