Albumin overload induces adaptive responses in human proximal tubular cells through oxidative stress but not via angiotensin II type 1 receptor.
Proteinuria is pathogenic to proximal tubular cells (PTC) and linked with progression to renal failure. The aim of this study was to determine the effects of human serum albumin (HSA) overload on the changes in gene and protein expression stimulated by oxidative stress in PTC and any interaction with ANG II that is pivotal in disease pathogenesis. Markers of oxidative stress, antioxidant defences, transcription factor activation, and the expression of stress-related genes were measured in human PTC (HK-2 cells) overloaded with either globulin-free fatty acid free (GF/FAF) HSA or globulin-free (GF) HSA. The effects of ANG II were also determined. HSA overload in HK-2 cells caused PTC hyperfunction, increased oxidative stress, and an upregulation of adaptive responses and stress-related genes. Some responses were common to both HSAs but others were unique to either HSA and unaffected by addition of ANG II or candesartan (a specific ANG II type 1 receptor blocker). ANG II also independently induced oxidative stress and upregulated other stress-related genes. HSA overload in HK-2 cells stimulated increased oxidative stress and upregulated changes in stress-related gene expression indicating new pathways of PTC injury that are not mediated via ANG II type 1 receptors.
Shalamanova
Liliana
L
School of Clinical Sciences, Division of Metabolic and Cellular Medicine, University of Liverpool, Liverpool, UK.
McArdle
Frank
F
Amara
Alieu B
AB
Jackson
Malcolm J
MJ
Rustom
Rana
R
D000222:Adaptation, Physiological / Q000187:drug effects; D000804:Angiotensin II / Q000494:pharmacology; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000975:Antioxidants / Q000378:metabolism; D001562:Benzimidazoles / Q000494:pharmacology; D001713:Biphenyl Compounds; D015153:Blotting, Western; D002460:Cell Line; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D048430:Cell Shape; D002470:Cell Survival / Q000187:drug effects; D018076:DNA, Complementary / Q000096:biosynthesis / Q000235:genetics; D004705:Endocytosis / Q000187:drug effects / Q000502:physiology; D007687:Kidney Tubules, Proximal / Q000166:cytology / Q000187:drug effects*; D050356:Lipid Metabolism / Q000187:drug effects; D015227:Lipid Peroxidation / Q000187:drug effects; D018384:Oxidative Stress / Q000235:genetics / Q000502:physiology*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D044140:Receptor, Angiotensin, Type 1 / Q000187:drug effects / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012709:Serum Albumin / Q000494:pharmacology*; D013438:Sulfhydryl Compounds / Q000378:metabolism; D013777:Tetrazoles / Q000494:pharmacology; D014157:Transcription Factors / Q000378:metabolism
D047228:Angiotensin II Type 1 Receptor Blockers; D000975:Antioxidants; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D018076:DNA, Complementary; D012333:RNA, Messenger; D044140:Receptor, Angiotensin, Type 1; D012709:Serum Albumin; D013438:Sulfhydryl Compounds; D013777:Tetrazoles; D014157:Transcription Factors; D000804:Angiotensin II; C081643:candesartan