PP.11.15: IMPACT OF NEONATAL LEPTIN ON RENAL STRUCTURE AND FUNCTION IN THE PRESENCE AND ABSENCE OF HYPERTENSION. (June 2015)

• Record Type: Journal Article
• Authors: Samuelsson, A.; Wylie, S.; Blasco, N. Maicas; Horsfield, C.; Pombo, J.; Poston, L.
• Is Part Of: Journal of hypertension. Volume 33(2015)Supplement 1
• Publication Date: 2015-06
• Subjects: Hypertension -- Periodicals; Hypertension -- Periodicals; 616.132005
• DOI: 10.1097/01.hjh.0000468047.89248.14
• Languages: English
• ISSNs: 1473-5598

Abstract

Abstract : Objective: Maternal obesity in rodents leads to sympathetic mediated hypertension in the juvenile offspring prior to obesity. This is associated with an exaggerated leptin surge in early postnatal life. The aim of this study was to determine the impact of this exaggerated neonatal leptin surge on the long-term renal structure and function, independent of the presence of hypertension, using a normotensive melanocortin-4 receptor deficient (MC4R -/-) mice model. Design and method: Neonatal mice were treated with leptin (L-Tx; 3 mg/kg IP) or saline (S-Tx), postnatal day 9–14. Mean arterial pressure (MAP) and glomerular filtration rate (GFR) were measured at 6 month old wild-type (WT) and MC4R (-/-) mice using radiotelemetry and creatinine clearance test respectively. After hypertension had been established in WT, markers of renal injury, intrarenal renin-angiotensin system and sodium transporters were assessed and compared with normotensive MC4R (-/-) mice. Results: At 6 months of age, obese MC4R (-/-) mice were hyperphagic and hyperleptinaemic compared with WT. Neonatal leptin (L-Tx) induced body weight, food intake and fat mass in WT with no influence in the MC4R (-/-) mice. L-Tx-WT mice showed also 30% less glomerular area and reduced creatinine clearance [GFR, ml/min gKW, L-Tx, 0.46 ± 0.06 vs. S-Tx, 1.34 ± 0.32, n = 6, p < 0.01] with no additive effect in the MC4R (-/-) mice. Renal injury was increased in L-Tx mice with higher urinary albumin excretion (UAE) and ratio UAE/creatinine in MC4R (-/-) compared with WT. The L-Tx WT mice showed greater expression of renal tyrosine hydroxylase (TH), angiotensin II receptor (AT1a) and renin with marked down-regulated angiotensin II 2 (AT2R). These alterations were associated with elevated proximal tubule Na-H exchanger 3 transporter. Interestingly L-Tx mice also demonstrated increased renal NADPH oxidase 4 (NOX-4) and cyclooxygenase 2 (COX-2) expression [COX-2, L-Tx, 458 ± 92 vs. S-Tx, 162 ± 37, n = 6, p < 0.01]. COX has been associated with angiotensin II induced hypertension and reactive oxygen species (ROS). Conclusions: Thus, alterations in MAP, Ang II pathways and ROS handling in the kidney, may reset the tubular functions in neonatal leptin mice and underpin the development of hypertension and renal dysfunction.