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Extravascular renal denervation ameliorates juvenile hypertension and renal damage resulting from experimental hyperleptinemia in rats

Oosterhuis, Nynke R.a; Fernandes, Ramonb; Maicas, Nuriab; Bae, Sung Eunb; Pombo, Joaquimb; Gremmels, Hendrika; Poston, Lucillab; Joles, Jaap A.a; Samuelsson, Anne-Majb

doi: 10.1097/HJH.0000000000001472
ORIGINAL PAPERS: Therapeutic aspects
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Background: Material obesity in rodents is associated with neonatal hyperleptinemia and hypertension of sympathetic origin in adult offspring. Previously, we reported that experimentally induced hyperleptinemia in rat pups results in adulthood hypertension. Here, we addressed the hypothesis that experimental neonatal hyperleptinemia, through renal nerve activation, adversely affects adult renal function.

Method: Sprague-Dawley male and female pups were treated with neonatal leptin (3 mg/kg, intraperitoneal) or neonatal saline, twice daily from postnatal day 9–14. Juvenile (1 month) neonatal leptin and neonatal saline rats were subjected to either bilateral renal denervation, unilateral renal denervation or Sham surgery. Arterial pressure was telemetrically monitored.

Results: Juvenile neonatal leptin rats with intact renal nerves demonstrated increased mean arterial pressure (MAP) accompanied by local renin–angiotensin system overactivity and reduced glomerular filtration rate. Bilateral renal denervation in rats protected against neonatal leptin-induced MAP, renal renin–angiotensin system and impaired glomerular filtration rate. A two-fold increase in sympathetically mediated tubulointerstitial damage in young adult (2 months) neonatal leptin females, was suppressed by unilateral renal denervation, independent of MAP. Neonatal leptin rats also demonstrated increases in urinary protein, neutrophil gelatinase-associated lipocalin, and kidney injury molecule-1. Raised blood pressure was associated with increased salt sensitivity and with sustained renal dysfunction in adulthood.

Conclusion: We propose that neonatal hyperleptinemia programmes long-term renal structural and functional damage, through renal sympathetic nerve activation.

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aDepartment of Nephrology and Hypertension, University Medical Center Utrecht, Utrecht, The Netherlands

bDivision of Women's Health, Women's Health Academic Centre KHP, King's College London, London, UK

Correspondence to Anne-Maj Samuelsson, PhD, Division of Women's Health, Women's Health Academic Centre KHP, St Thomas’ Hospital, Kings College London, 10th Floor North Wing, London SE1 7EH, UK. Tel: +44 20 71883630; fax: +44 20 7620 1227; e-mail: anne-maj.samuelsson@kcl.ac.uk

Abbreviations: BRDN, bilateral renal denervation; GFR, glomerular filtration rate; KIM-1, kidney injury molecule-1; NGAL, neutrophil gelatinase-associated lipocalin; Nox-4, NADPH oxidase-4; RDN, renal sympathetic denervation; URDN, unilateral renal denervation

Received 5 April, 2017

Revised 8 May, 2017

Accepted 13 June, 2017

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