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

doi:10.1016/j.kint.2020.03.039

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

Kidney Int. 2020 Oct;98(4):906-917. doi: 10.1016/j.kint.2020.03.039. Epub 2020 Apr 25.

Authors

Affiliations

¹ Neuropharmacology Laboratory, Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia; Human Neurotransmitters Laboratory, Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia; Faculty of Medicine, Nursing and Health Sciences, Central Clinical School, Monash University, Melbourne, Victoria, Australia; Department of Cardiology, Alfred Hospital, Melbourne, Victoria, Australia.
² Neuropharmacology Laboratory, Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia.
³ Department of Diabetes, Central Clinical School, Monash University, Melbourne, Victoria, Australia.
⁴ Human Neurotransmitters Laboratory, Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia; Iverson Health Innovation Research Institute and School of Health Science, Swinburne University of Technology, Hawthorn, Victoria, Australia.
⁵ Neuropharmacology Laboratory, Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia; Department of Physiology, Anatomy and Microbiology, La Trobe University, Melbourne, Victoria, Australia.
⁶ Department of Diabetes, Central Clinical School, Monash University, Melbourne, Victoria, Australia; German Diabetes Centre, Leibnitz Institute for Diabetes Research at the Heinrich Heine University, Dusseldorf, Germany.
⁷ Monash Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia.
⁸ Human Neurotransmitters Laboratory, Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia; Faculty of Medicine, Nursing and Health Sciences, Central Clinical School, Monash University, Melbourne, Victoria, Australia; Department of Cardiology, Alfred Hospital, Melbourne, Victoria, Australia.
⁹ Human Neurotransmitters Laboratory, Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia; Dobney Hypertension Centre, School of Medicine, Royal Perth Hospital Unit, University of Western Australia and Departments of Cardiology and Nephrology, Royal Perth Hospital, Perth, Western Australia, Australia.
¹⁰ Neuropharmacology Laboratory, Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia; Department of Pharmacology, Monash University, Melbourne, Victoria, Australia. Electronic address: geoff.head@baker.edu.au.

PMID: 32763117
DOI: 10.1016/j.kint.2020.03.039

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 5/6^th 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.

Keywords: blood pressure; chronic kidney disease; hypertension; rabbit; sympathetic nervous system.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Baroreflex
Blood Pressure
Heart Rate
Kidney
Rabbits
Renal Insufficiency, Chronic*
Sympathetic Nervous System