Renal oxidative stress induced by long-term hyperuricemia alters mitochondrial function and maintains systemic hypertension.
We addressed if oxidative stress in the renal cortex plays a role in the induction of hypertension and mitochondrial alterations in hyperuricemia. A second objective was to evaluate whether the long-term treatment with the antioxidant Tempol prevents renal oxidative stress, mitochondrial alterations, and systemic hypertension in this model. Long-term (11-12 weeks) and short-term (3 weeks) effects of oxonic acid induced hyperuricemia were studied in rats (OA, 750 mg/kg BW), OA+Allopurinol (AP, 150 mg/L drinking water), OA+Tempol (T, 15 mg/kg BW), or vehicle. Systolic blood pressure, renal blood flow, and vascular resistance were measured. Tubular damage (urine N-acetyl-β-D-glucosaminidase) and oxidative stress markers (lipid and protein oxidation) along with ATP levels were determined in kidney tissue. Oxygen consumption, aconitase activity, and uric acid were evaluated in isolated mitochondria from renal cortex. Short-term hyperuricemia resulted in hypertension without demonstrable renal oxidative stress or mitochondrial dysfunction. Long-term hyperuricemia induced hypertension, renal vasoconstriction, tubular damage, renal cortex oxidative stress, and mitochondrial dysfunction and decreased ATP levels. Treatments with Tempol and allopurinol prevented these alterations. Renal oxidative stress induced by hyperuricemia promoted mitochondrial functional disturbances and decreased ATP content, which represent an additional pathogenic mechanism induced by chronic hyperuricemia. Hyperuricemia-related hypertension occurs before these changes are evident.
Department of Nephrology, INC Ignacio Chávez, 14080 Mexico City, DF, Mexico.
Magdalena
M
Cristóbal-García
Department of Nephrology, INC Ignacio Chávez, 14080 Mexico City, DF, Mexico ; Laboratory of Renal Physiopathology, INC Ignacio Chávez, 14080 Mexico City, DF, Mexico.
Fernando E
FE
García-Arroyo
Department of Nephrology, INC Ignacio Chávez, 14080 Mexico City, DF, Mexico ; Laboratory of Renal Physiopathology, INC Ignacio Chávez, 14080 Mexico City, DF, Mexico.
Edilia
0000-0002-9718-6854
E
Tapia
Department of Nephrology, INC Ignacio Chávez, 14080 Mexico City, DF, Mexico ; Laboratory of Renal Physiopathology, INC Ignacio Chávez, 14080 Mexico City, DF, Mexico.
Horacio
0000-0002-9238-4202
H
Osorio
Department of Nephrology, INC Ignacio Chávez, 14080 Mexico City, DF, Mexico ; Laboratory of Renal Physiopathology, INC Ignacio Chávez, 14080 Mexico City, DF, Mexico.
Abraham S
AS
Arellano-Buendía
Department of Nephrology, INC Ignacio Chávez, 14080 Mexico City, DF, Mexico.
Magdalena
M
Madero
Division of Nephrology, Hospital Universitario de Maracaibo and Laboratory of Immunobiology, Instituto Venezolano Investigaciones Científicas, Maracaibo 04011, Zulia, Venezuela.
Bernardo
B
Rodríguez-Iturbe
Department of Biology, Facultad de Química UNAM, 04510 Mexico City, DF, Mexico.
José
J
Pedraza-Chaverrí
Department of Cardiovascular Biomedicine, INC Ignacio Chávez, 14080 Mexico City, DF, Mexico.
Francisco
0000-0002-4243-6019
F
Correa
Department of Cardiovascular Biomedicine, INC Ignacio Chávez, 14080 Mexico City, DF, Mexico.
Cecilia
C
Zazueta
Division of Renal Diseases and Hypertension, University of Colorado, Denver, CO 80045, USA.
Richard J
RJ
Johnson
Department of Nephrology, INC Ignacio Chávez, 14080 Mexico City, DF, Mexico ; Laboratory of Renal Physiopathology, INC Ignacio Chávez, 14080 Mexico City, DF, Mexico.
Laura-Gabriela Sánchez
LG
Lozada
D000255:Adenosine Triphosphate / Q000378:metabolism; D000493:Allopurinol / Q000494:pharmacology; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D003497:Cyclic N-Oxides / Q000494:pharmacology; D004195:Disease Models, Animal; D006973:Hypertension / Q000209:etiology / Q000473:pathology*; D033461:Hyperuricemia / Q000139:chemically induced / Q000150:complications / Q000473:pathology*; D007668:Kidney / Q000098:blood supply / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects; D010094:Oxonic Acid / Q000633:toxicity; D010101:Oxygen Consumption; D051381:Rats; D017207:Rats, Sprague-Dawley; D012079:Renal Circulation / Q000187:drug effects; D013113:Spin Labels; D013997:Time Factors
D000975:Antioxidants; D003497:Cyclic N-Oxides; D013113:Spin Labels; D010094:Oxonic Acid; D000493:Allopurinol; D000255:Adenosine Triphosphate; C001803:tempol