title: Hypertension and hyperglycemia synergize to cause incipient renal tubular alterations resulting in increased NGAL urinary excretion in rats.
abstract: BACKGROUND
  Hypertension and diabetes are the two leading causes of chronic kidney disease (CKD) eventually leading to end stage renal disease (ESRD) and the need of renal replacement therapy. Mortality among CKD and ESRD patients is high, mostly due to cardiovascular events. New early markers of risk are necessary to better anticipate the course of the disease, to detect the renal affection of additive risk factors, and to appropriately handle patients in a pre-emptive and personalized manner.
  
  
  METHODS
  Renal function and NGAL urinary excretion was monitored in rats with spontaneous (SHR) or L-NAME induced hypertension rendered hyperglycemic (or not as controls).
  
  
  RESULTS
  Combination of hypertension and hyperglycemia (but not each of these factors independently) causes an increased urinary excretion of neutrophil gelatinase-associated lipocalin (NGAL) in the rat, in the absence of signs of renal damage. Increased NGAL excretion is observed in diabetic animals with two independent models of hypertension. Elevated urinary NGAL results from a specific alteration in its tubular handling, rather than from an increase in its renal expression. In fact, when kidneys of hyperglycaemic-hypertensive rats are perfused in situ with Krebs-dextran solution containing exogenous NGAL, they excrete more NGAL in the urine than hypertensive rats. We also show that albuminuria is not capable of detecting the additive effect posed by the coexistence of these two risk factors.
  
  
  CONCLUSIONS
  Our results suggest that accumulation of hypertension and hyperglycemia induces an incipient and quite specific alteration in the tubular handling of NGAL resulting in its increased urinary excretion.
authors.affiliation: Departamento de Fisiología y Farmacología, Universidad de Salamanca, Salamanca, Spain; Instituto Reina Sofía de Investigación Nefrológica, Fundación Iñigo Álvarez de Toledo, Madrid, Spain.
authors.forename: Ana M
authors.initials: AM
authors.lastname: Blázquez-Medela
authors.affiliation: Departamento de Fisiología y Farmacología, Universidad de Salamanca, Salamanca, Spain; Instituto Reina Sofía de Investigación Nefrológica, Fundación Iñigo Álvarez de Toledo, Madrid, Spain.
authors.forename: Omar
authors.initials: O
authors.lastname: García-Sánchez
authors.affiliation: Instituto de Estudios de Ciencias de la Salud de Castilla y León-Instituto de Investigación Biomédica de Salamanca (IECSCYL-IBSAL), Unidad de Investigación, Hospital Universitario de Salamanca, Salamanca, Spain; Departamento de Fisiología y Farmacología, Universidad de Salamanca, Salamanca, Spain; Bio-inRen, S.L., Salamanca, Spain.
authors.forename: Víctor
authors.initials: V
authors.lastname: Blanco-Gozalo
authors.affiliation: Departamento de Fisiología y Farmacología, Universidad de Salamanca, Salamanca, Spain; Bio-inRen, S.L., Salamanca, Spain.
authors.forename: Yaremi
authors.initials: Y
authors.lastname: Quiros
authors.affiliation: Departamento de Fisiología y Farmacología, Universidad de Salamanca, Salamanca, Spain.
authors.forename: María J
authors.initials: MJ
authors.lastname: Montero
authors.affiliation: Instituto de Estudios de Ciencias de la Salud de Castilla y León-Instituto de Investigación Biomédica de Salamanca (IECSCYL-IBSAL), Unidad de Investigación, Hospital Universitario de Salamanca, Salamanca, Spain; Departamento de Fisiología y Farmacología, Universidad de Salamanca, Salamanca, Spain; Instituto Reina Sofía de Investigación Nefrológica, Fundación Iñigo Álvarez de Toledo, Madrid, Spain.
authors.forename: Carlos
authors.initials: C
authors.lastname: Martínez-Salgado
authors.affiliation: Departamento de Fisiología y Farmacología, Universidad de Salamanca, Salamanca, Spain; Instituto Reina Sofía de Investigación Nefrológica, Fundación Iñigo Álvarez de Toledo, Madrid, Spain.
authors.forename: José M
authors.initials: JM
authors.lastname: López-Novoa
authors.affiliation: Instituto de Estudios de Ciencias de la Salud de Castilla y León-Instituto de Investigación Biomédica de Salamanca (IECSCYL-IBSAL), Unidad de Investigación, Hospital Universitario de Salamanca, Salamanca, Spain; Departamento de Fisiología y Farmacología, Universidad de Salamanca, Salamanca, Spain; Instituto Reina Sofía de Investigación Nefrológica, Fundación Iñigo Álvarez de Toledo, Madrid, Spain.
authors.forename: Francisco J
authors.initials: FJ
authors.lastname: López-Hernández
mesh_terms: D000209:Acute-Phase Proteins / Q000235:genetics / Q000652:urine*; D000818:Animals; D015415:Biomarkers / Q000652:urine; D001794:Blood Pressure; D003921:Diabetes Mellitus, Experimental / Q000503:physiopathology*; D006943:Hyperglycemia / Q000503:physiopathology*; D006973:Hypertension / Q000139:chemically induced / Q000503:physiopathology*; D007684:Kidney Tubules / Q000378:metabolism / Q000503:physiopathology*; D000071068:Lipocalin-2; D054834:Lipocalins / Q000235:genetics / Q000652:urine*; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000633:toxicity; D010477:Perfusion; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000652:urine*; D011918:Rats, Inbred SHR; D017208:Rats, Wistar
chemical_list: D000209:Acute-Phase Proteins; D015415:Biomarkers; C097278:Lcn2 protein, rat; D000071068:Lipocalin-2; D054834:Lipocalins; D011518:Proto-Oncogene Proteins; D019331:NG-Nitroarginine Methyl Ester