Differential sympathetic response to lesion-induced chronic kidney disease in rabbits

Yusuke Sata, Sandra L. Burke, Anna M.D. Watson, Jay C. Jha, Cindy Gueguen, Nina Eikelis, Kyungjoon Lim, Kristy L. Jackson, Gavin W. Lambert, Karin A.M. Jandeleit-Dahm, Kate M. Denton, Murray D. Esler, Markus P. Schlaich, Geoffrey A. Head

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Abstract

Chronic kidney disease (CKD) is associated with greater sympathetic nerve activity but it is unclear if this is a kidney-specific response or due to generalized stimulation of sympathetic nervous system activity. To determine this, we used a rabbit model of CKD in which quantitative comparisons with control rabbits could be made of kidney sympathetic nerve activity and whole-body norepinephrine spillover. Rabbits either had surgery to lesion 5/6th of the cortex of one kidney by electro-lesioning and two weeks later removal of the contralateral kidney, or sham lesioning and sham nephrectomy. After three weeks, the blood pressure was statistically significantly 20% higher in conscious rabbits with CKD compared to rabbits with a sham operation, but their heart rate was similar. Strikingly, kidney nerve activity was 37% greater than in controls, with greater burst height and frequency. Total norepinephrine spillover was statistically significantly lower by 34%, and kidney baroreflex curves were shifted to the right in rabbits with CKD. Plasma creatinine and urine output were elevated by 38% and 131%, respectively, and the glomerular filtration rate was 37% lower than in sham-operated animals (all statistically significant). Kidney gene expression of fibronectin, transforming growth factor-β, monocyte chemotactic protein1, Nox4 and Nox5 was two- to eight-fold greater in rabbits with CKD than in control rabbits. Overall, the glomerular layer lesioning model in conscious rabbits produced a moderate, stable degree of CKD characterized by elevated blood pressure and increased kidney sympathetic nerve activity. Thus, our findings, together with that of a reduction in total norepinephrine spillover, suggest that kidney denervation, rather than generalized sympatholytic treatments, may represent a preferable management for CKD associated hypertension.

Original languageEnglish
Pages (from-to)906-917
Number of pages12
JournalKidney International
Volume98
Issue number4
DOIs
Publication statusPublished - 1 Oct 2020

Keywords

  • blood pressure
  • chronic kidney disease
  • hypertension
  • rabbit
  • sympathetic nervous system

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