title: Perinatal Inhibition of NF-KappaB Has Long-Term Antihypertensive and Renoprotective Effects in Fawn-Hooded Hypertensive Rats.
abstract: BACKGROUND
  Inhibition of transcription factor nuclear factor-kappa B (NFκB) is beneficial in various models of hypertension and renal disease. We hypothesized first that NFκB inhibition during renal development ameliorates hereditary hypertensive renal disease and next whether this was mediated via suppression of peroxisome proliferator-activated receptor (PPAR)γ coactivator 1α (PGC-1α).
  
  
  RESULTS
  Prior to the development of renal injury in fawn-hooded hypertensive (FHH) rats, a model of hypertension, glomerular hyperfiltration, and progressive renal injury, NFkB activity, measured by nuclear protein expression of NFkB subunit p65, was enhanced twofold in 2-day-old male and female FHH kidneys as compared to normotensive Wistar-Kyoto (WKY) rats (P < 0.05). Treating FHH dams with pyrrolidine di thio carbamate (PDTC), an NFκB inhibitor, from 2 weeks before birth to 4 weeks after birth diminished NFkB activity in 2-day-FHH offspring to 2-day-WKY levels (P < 0.01). Perinatal PDTC reduced systolic blood pressure from 20 weeks onwards by on average 25 mm Hg (P < 0.001) and ameliorated proteinuria (P < 0.05) and glomerulosclerosis (P < 0.05). In kidneys of 2-day-, 2-week-, and adult offspring of PDTC-treated FHH dams, PGC-1α was induced on average by 67% (quantitative polymerase chain reaction (qPCR)) suggesting that suppression of this factor by NFkB could be involved in renal damage. Follow-up experiments with perinatal pioglitazone (Pio), a PPARγ agonist, failed to confer persistent antihypertensive or renoprotective effects.
  
  
  CONCLUSIONS
  Perinatal inhibition of enhanced active renal NFκB in 2-day FHH had persistent antihypertensive and renoprotective effects. However, this was not the case for PPARγ stimulation. NFkB stimulation is therefore involved in renal damage in the FHH model of proteinuric renal disease by pathways other than via PPARγ.
authors.affiliation: Department of Nephrology and Hypertension, University Medical Center, Utrecht, Netherlands; School of Physiology and Pharmacology, University of Bristol, Bristol, UK;
authors.forename: Maarten P
authors.initials: MP
authors.lastname: Koeners
authors.affiliation: Department of Nephrology and Hypertension, University Medical Center, Utrecht, Netherlands; Division of Toxicology, Wageningen University, Wageningen, The Netherlands;
authors.forename: Sebastiaan
authors.initials: S
authors.lastname: Wesseling
authors.affiliation: Department of Nephrology and Hypertension, University Medical Center, Utrecht, Netherlands; Department of Pharmacology, School of Pharmacy, University of Granada, Spain;
authors.forename: Manuel
authors.initials: M
authors.lastname: Sánchez
authors.affiliation: Division of Nephrology & Immunology, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada; Department of Physiology, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Branko
authors.initials: B
authors.lastname: Braam
authors.affiliation: Department of Nephrology and Hypertension, University Medical Center, Utrecht, Netherlands; j.a.joles@umcutrecht.nl.
authors.forename: Jaap A
authors.initials: JA
authors.lastname: Joles
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D000959:Antihypertensive Agents / Q000627:therapeutic use*; D001794:Blood Pressure / Q000187:drug effects; D004195:Disease Models, Animal; D005260:Female; D018507:Gene Expression Regulation, Developmental; D006977:Hypertension, Renal / Q000150:complications / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control; D008297:Male; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics*; D009393:Nephritis / Q000235:genetics / Q000503:physiopathology / Q000517:prevention & control*; D012313:RNA / Q000235:genetics*; D051381:Rats; D011921:Rats, Inbred WKY; D012079:Renal Circulation
chemical_list: D000959:Antihypertensive Agents; D016328:NF-kappa B; D012313:RNA
keywords: blood pressure; developmental plasticity; glomerulosclerosis; hypertension; nuclear factor-kappa B; renal hemodynamics.