title: The effect of aliskiren on urinary cytokine/chemokine responses to clamped hyperglycaemia in type 1 diabetes.
abstract: OBJECTIVE
  Acute clamped hyperglycaemia activates the renin-angiotensin-aldosterone system (RAAS) and increases the urinary excretion of inflammatory cytokines/chemokines in patients with uncomplicated type 1 diabetes mellitus. Our objective was to determine whether blockade of the RAAS would blunt the effect of acute hyperglycaemia on urinary cytokine/chemokine excretion, thereby giving insights into potentially protective effects of these agents prior to the onset of clinical nephropathy.
  
  
  METHODS
  Blood pressure, renal haemodynamic function (inulin and para-aminohippurate clearances) and urinary cytokines/chemokines were measured after 6 h of clamped euglycaemia (4-6 mmol/l) and hyperglycaemia (9-11 mmol/l) on two consecutive days in patients with type 1 diabetes mellitus (n = 27) without overt nephropathy. Measurements were repeated after treatment with aliskiren (300 mg daily) for 30 days.
  
  
  RESULTS
  Before aliskiren, clamped hyperglycaemia increased filtration fraction (from 0.188 ± 0.007 to 0.206 ± 0.007, p = 0.003) and urinary fibroblast growth factor-2 (FGF2), IFN-α2 and macrophage-derived chemokine (MDC) (p < 0.005). After aliskiren, the filtration fraction response to hyperglycaemia was abolished, resulting in a lower filtration fraction after aliskiren under clamped hyperglycaemic conditions (p = 0.004), and none of the biomarkers increased in response to hyperglycaemia. Aliskiren therapy also reduced levels of urinary eotaxin, FGF2, IFN-α2, IL-2 and MDC during clamped hyperglycaemia (p < 0.005).
  
  
  CONCLUSIONS
  The increased urinary excretion of inflammatory cytokines/chemokines in response to acute hyperglycaemia is blunted by RAAS blockade in humans with uncomplicated type 1 diabetes mellitus.
authors.affiliation: Division of Nephrology, University Health Network - Toronto General Hospital, Banting and Best Diabetes Centre, University of Toronto, 585 University Ave, 8N-845, Toronto, ON M5G 2N2, Canada. david.cherney@uhn.on.ca
authors.forename: David Z I
authors.initials: DZ
authors.lastname: Cherney
authors.forename: Heather N
authors.initials: HN
authors.lastname: Reich
authors.forename: James W
authors.initials: JW
authors.lastname: Scholey
authors.forename: Denis
authors.initials: D
authors.lastname: Daneman
authors.forename: Farid H
authors.initials: FH
authors.lastname: Mahmud
authors.forename: Ronnie L H
authors.initials: RL
authors.lastname: Har
authors.forename: Etienne B
authors.initials: EB
authors.lastname: Sochett
mesh_terms: D000328:Adult; D000577:Amides / Q000627:therapeutic use*; D018925:Chemokines / Q000652:urine*; D016207:Cytokines / Q000652:urine*; D003922:Diabetes Mellitus, Type 1 / Q000188:drug therapy* / Q000378:metabolism*; D005260:Female; D005650:Fumarates / Q000627:therapeutic use*; D006801:Humans; D006943:Hyperglycemia / Q000188:drug therapy* / Q000378:metabolism*; D007328:Insulin / Q000627:therapeutic use; D008297:Male; D040901:Proteomics; D055815:Young Adult; D010130:p-Aminohippuric Acid / Q000627:therapeutic use
chemical_list: D000577:Amides; D018925:Chemokines; D016207:Cytokines; D005650:Fumarates; D007328:Insulin; C446481:aliskiren; D010130:p-Aminohippuric Acid
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