title: Obesity and hypertension have differing oxidant handling molecular pathways in age-related chronic kidney disease.
abstract: Chronic kidney disease (CKD) in ageing is a burden on health systems worldwide. Rat models of age-related CKD linked with obesity and hypertension were used to investigate alterations in oxidant handling and energy metabolism to identify gene targets or markers for age-related CKD. Young adult (3 months) and old (21-24 months) spontaneously-hypertensive (SHR), normotensive Wistar-Kyoto (WKY) and Wistar rats (normotensive, obese in ageing) were compared for renal functional and physiological parameters, renal fibrosis and inflammation, oxidative stress (hemeoxygenase-1/HO-1), apoptosis and cell injury (including Bax:Bcl-2), phosphorylated and non-phosphorylated forms of oxidant and energy sensing proteins (p66Shc, AMPK), signal transduction proteins (ERK1/2, PKB), and transcription factors (NF-kappaB, FoxO1). All old rats were normoglycemic. Renal fibrosis, tubular epithelial apoptosis, interstitial macrophages and myofibroblasts (all p<0.05), p66Shc/phospho-p66 (p<0.05), Bax/Bcl-2 ratio (p<0.05) and NF-kappaB expression (p<0.01) were highest in old obese Wistars. Expression of phospho-FoxO/FoxO was elevated in old Wistars (p<0.001) and WKYs (p<0.01). SHRs had high levels in young and old rats. Expression of PKB, phospho-PKB, ERK1/2 and phospho-ERK1/2 were significantly elevated in all aged animals. These results suggest that obesity and hypertension have differing oxidant handling and signalling pathways that act in the pathogenesis of age-related CKD.
authors.affiliation: Molecular & Cellular Pathology, School of Medicine, The University of Queensland, Brisbane, Australia. c.percy@uq.edu.au
authors.forename: C J
authors.initials: CJ
authors.lastname: Percy
authors.forename: L
authors.initials: L
authors.lastname: Brown
authors.forename: D A
authors.initials: DA
authors.lastname: Power
authors.forename: D W
authors.initials: DW
authors.lastname: Johnson
authors.forename: G C
authors.initials: GC
authors.lastname: Gobe
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D050154:Adiposity; D000367:Age Factors; D000375:Aging / Q000378:metabolism*; D000818:Animals; D001343:Autophagy; D001835:Body Weight; D002908:Chronic Disease; D004195:Disease Models, Animal; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005355:Fibrosis; D051858:Forkhead Transcription Factors / Q000378:metabolism; D006419:Heme Oxygenase (Decyclizing) / Q000378:metabolism; D006973:Hypertension / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D007668:Kidney / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D007674:Kidney Diseases / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D007770:L-Lactate Dehydrogenase / Q000097:blood; D008297:Male; D016328:NF-kappa B / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009765:Obesity / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D016877:Oxidants / Q000378:metabolism*; D018384:Oxidative Stress; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D055765:Shc Signaling Adaptor Proteins / Q000378:metabolism; D015398:Signal Transduction; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D051028:bcl-2-Associated X Protein / Q000378:metabolism; D000071161:Forkhead Box Protein O1
chemical_list: D055372:AMP-Activated Protein Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D051858:Forkhead Transcription Factors; D006419:Heme Oxygenase (Decyclizing); D007770:L-Lactate Dehydrogenase; D016328:NF-kappa B; D009419:Nerve Tissue Proteins; D016877:Oxidants; D051057:Proto-Oncogene Proteins c-akt; D019253:Proto-Oncogene Proteins c-bcl-2; D055765:Shc Signaling Adaptor Proteins; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D051028:bcl-2-Associated X Protein; C494828:Bax protein, rat; C528035:Shc1 protein, rat; C074639:Foxo1 protein, rat; D000071161:Forkhead Box Protein O1; C491523:Hmox1 protein, rat