Role of heme oxygenase in the regulation of the renal hemodynamics in a model of sex-dependent programmed hypertension by maternal diabetes

• Published in: American journal of physiology. Regulatory, integrative and comparative physiology Vol. 322; no. 3; pp. R181 - R191
• Main Authors: Martínez-Gascón, Lidia E, Ortiz, María Clara, Galindo, María, Sanchez, Jose Miguel, Sancho-Rodríguez, Natalia, Albaladejo-Otón, María Dolores, Rodríguez Mulero, María Dolores, Rodriguez, Francisca
• Format: Journal Article
• Language: English
• Published: United States American Physiological Society 01.03.2022
• Subjects: Animals; Antioxidants; Blood pressure; Cardiovascular system; Diabetes; Diabetes mellitus; Diabetes Mellitus, Experimental - complications; Diabetes Mellitus, Experimental - enzymology; Diabetes Mellitus, Experimental - physiopathology; Diabetes, Gestational - enzymology; Diabetes, Gestational - physiopathology; Endothelium; Female; Glomerular filtration rate; Heme; Heme oxygenase (decyclizing); Heme Oxygenase (Decyclizing) - metabolism; Hemodynamics; Hypertension; Hypertension - enzymology; Hypertension - etiology; Hypertension - physiopathology; Kidney - blood supply; Kidney - enzymology; Male; Males; Nitric oxide; Nitrotyrosine; Offspring; Oxidative Stress; Oxygenase; Phenylephrine; Pregnancy; Prenatal Exposure Delayed Effects; Rats; Rats, Sprague-Dawley; Renal Circulation; Renal function; Sex; Sex Factors; Streptozocin; Tempol; heme oxygenase; fetal programming; renal hemodynamics; oxidative stress; sex differences
• ISSN: 0363-6119; 1522-1490
• DOI: 10.1152/AJPREGU.00213.2021

Intrauterine programming of cardiovascular and renal function occurs in diabetes because of the adverse maternal environment. Heme oxygenase 1 (HO-1) and -2 (HO-2) exert vasodilatory and antioxidant actions, particularly in conditions of elevated HO-1 expression or deficient nitric oxide levels. We evaluated whether the activity of the heme-HO system is differentially regulated by oxidative stress in the female offspring of diabetic mothers, contributing to the improved cardiovascular function in comparison with males. Diabetes was induced in pregnant rats by a single dose of streptozotocin (STZ, 50 mg/kg ip) in late gestation. Three-month-old male offspring from diabetic mothers (MODs) exhibited higher blood pressure (BP), higher renal vascular resistance (RVR), worse endothelium-dependent response to acetylcholine (ACH), and an increased constrictor response to phenylephrine (PHE) compared with those in age-matched female offspring of diabetic mothers (FODs), which were abolished by chronic tempol (1 mM) treatment. In anesthetized animals, stannous mesoporphyrin (SnMP; 40 µmol/kg iv) administration, to inhibit HO activity, increased RVR in FODs and reduced glomerular filtration rate (GFR) in MODs, without altering these parameters in control animals. When compared with MODs, FODs showed lower nitrotirosyne levels and higher HO-1 protein expression in renal homogenates. Indeed, chronic treatment with tempol in MODs prevented elevations in nitrotyrosine levels and the acute renal hemodynamics response to SnMP. Then, maternal diabetes results in sex-specific hypertension and renal alterations associated with oxidative stress mainly in adult male offspring, which are reduced in the female offspring by elevation in HO-1 expression and lower oxidative stress levels.