Cardiac Inflammation after Ischemia-Reperfusion of the Kidney: Role of the Sympathetic Nervous System and the Renin-Angiotensin System

Cell Physiol Biochem. 2019;53(4):587-605. doi: 10.33594/000000159.

Abstract

Background/aims: To investigate the role of the sympathetic nervous system (SNS) and renin-angiotensin system (RAS) in renal ischemia/reperfusion-induced (I/R) cardiac inflammatoryprofile.

Methods: Left kidney ischemia was induced in male C57BL/6 mice for 60 min, followed by reperfusion for 12 days, and treatment with or without atenolol, losartan, or enalapril. The expression of vimentin in kidney and atrial natriuretic factor (ANF) in the heart has been investigated by RT-PCR. In cardiac tissue, levels of β1-adrenoreceptors, adenylyl cyclase, cyclic AMP-dependent protein kinase (PKA), noradrenaline, adrenaline (components of SNS), type 1 angiotensin II receptors (AT1R), angiotensinogen/Ang II and renin (components of RAS) have been measured by Western blotting and HPLC analysis. A panel of cytokines - tumour necrosis factor (TNF-α), interleukin IL-6, and interferon gamma (IFN-γ) - was selected as cardiac inflammatory markers.

Results: Renal vimentin mRNA levels increased by >10 times in I/R mice, indicative of kidney injury. ANF, a marker of cardiac lesion, increased after renal I/R, the values being restored to the level of Sham group after atenolol or enalapril treatment. The cardiac inflammatory profile was confirmed by the marked increase in the levels of mRNAs of TNF-α, IL-6, and IFN-γ. Atenolol and losartan reversed the upregulation of TNF-α expression, whereas enalapril restored IL-6 levels to Sham levels; both atenolol and enalapril normalized IFN-γ levels. I/R mice showed upregulation of β1-adrenoreceptors, adenylyl cyclase, PKA and noradrenaline. Renal I/R increased cardiac levels of AT1R, which decreased after losartan or enalapril treatment. Renin expression also increased, with the upregulation returning to Sham levels after treatment with SNS and RAS blockers. Angiotensinogen/Ang II levels in heart were unaffected by renal I/R, but they were significantly decreased after treatment with losartan and enalapril, whereas increase in renin levels decreased.

Conclusion: Renal I/R-induced cardiac inflammatory events provoked by the simultaneous upregulation of SNS and RAS in the heart, possibly underpin the mechanism involved in the development of cardiorenal syndrome.

Keywords: Cardiac hypertrophy; Inflammatory cytokines; Renal ischemia/reperfusion; Renin-angiotensin system; Sympathetic nervous system.

MeSH terms

  • Animals
  • Atenolol / pharmacology
  • Atenolol / therapeutic use
  • Atrial Natriuretic Factor / genetics
  • Atrial Natriuretic Factor / metabolism
  • Catecholamines / metabolism
  • Enalapril / pharmacology
  • Enalapril / therapeutic use
  • Interleukin-6 / metabolism
  • Kidney / metabolism*
  • Losartan / pharmacology
  • Losartan / therapeutic use
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Myocardium / metabolism*
  • Receptor, Angiotensin, Type 1 / genetics
  • Receptor, Angiotensin, Type 1 / metabolism
  • Receptors, Adrenergic, beta-1 / genetics
  • Receptors, Adrenergic, beta-1 / metabolism
  • Renin-Angiotensin System* / drug effects
  • Reperfusion Injury / drug therapy
  • Reperfusion Injury / metabolism
  • Reperfusion Injury / pathology
  • Sympathetic Nervous System / drug effects
  • Sympathetic Nervous System / metabolism*
  • Tumor Necrosis Factor-alpha / metabolism
  • Up-Regulation / drug effects
  • Vimentin / genetics
  • Vimentin / metabolism

Substances

  • Catecholamines
  • Interleukin-6
  • Receptor, Angiotensin, Type 1
  • Receptors, Adrenergic, beta-1
  • Tumor Necrosis Factor-alpha
  • Vimentin
  • Atenolol
  • Enalapril
  • Atrial Natriuretic Factor
  • Losartan