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AKI to CKD Transition is driven by Alpha 2 Adrenergic Receptors
Author(s) -
Jang HeeSeong,
Padanilam Babu
Publication year - 2019
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2019.33.1_supplement.566.5
Subject(s) - fibrosis , medicine , inflammation , kidney , kidney disease , endocrinology , acute kidney injury , receptor
Background Enhanced tissue level and activity of norepinephrine (NE) have been recognized as risk factors of development and progression of chronic kidney disease (CKD). Our reports showed renal denervation (DNx) can prevent renal fibrosis and inflammation in renal fibrogenesis models. However, the underlying mechanism by which renal DNx prevents the long‐term sequelae of acute kidney injury (AKI) remains to be elucidated. Methods Based on our published data, we hypothesized that NE mediates its effect through activation of alpha 2 adrenergic receptors (α 2 ‐ARs). In this study, we investigated whether genetic and/or pharmacological inhibition of α 2 ‐ARs prevents ischemia/reperfusion injury (IRI)‐induced inflammation and CKD progression. Results Renal bilateral IRI resulted in severe kidney fibrosis in medullary region over 2 weeks with persistent tubular injury and massive macrophage infiltration. Renal DNx suppressed renal inflammation, tubular damage, and fibrosis progression, as well as increase in blood pressure, 2 weeks post‐IRI. Pharmacological inhibition of α 2 ‐AR also inhibited fibrosis progression with reduced downstream targets of NE‐α 2 ‐AR axis, including angiotensinogen and fibrogenic factors. Consistent with results in renal DNx and pharmacological inhibition of α 2 ‐AR, inhibition of α 2A ‐ and α 2C ‐AR subtypes by pharmacological or genetic manipulation additively prevented macrophage accumulation with downregulation of M1 and M2 macrophage markers, resulting in suppression of persistent renal tubular injury and fibrosis progression. Conclusion Taken together, blockage of α 2 ‐AR subtypes prevents IRI‐induced AKI to CKD transition through inhibition of macrophage accumulation, persistent renal tubular injury and fibrosis progression, suggesting that targeting α 2 ‐ARs may be a potential therapeutic strategy to prevent long‐term sequelae of ischemic AKI. Support or Funding Information This work was supported by NIH DK‐083291 and DK‐090332 and UNMC College of Medicine Bridge fund. This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .