Abstract
The kidney is innervated by afferent sensory and efferent sympathetic nerve fibers. Norepinephrine (NE) is the primary neurotransmitter for post-ganglionic sympathetic adrenergic nerves, and its signaling, regulated through adrenergic receptors (AR), modulates renal function and pathophysiology under disease conditions. Renal sympathetic overactivity and increased NE level are commonly seen in chronic kidney disease (CKD) and are critical factors in the progression of renal disease. Blockade of sympathetic nerve-derived signaling by renal denervation or AR blockade in clinical and experimental studies demonstrates that renal nerves and its downstream signaling contribute to progression of acute kidney injury (AKI) to CKD and fibrogenesis. This review summarizes our current knowledge of the role of renal sympathetic nerve and adrenergic receptors in AKI, AKI to CKD transition and CKDand provides new insights into the therapeutic potential of intervening in its signaling pathways.
Highlights
Acute kidney injury (AKI) is associated with increased mortality and risk of development of chronic kidney disease (CKD) in the long term [1,2]
We reported that RDNx prevented the development of tubulointerstitial fibrogenesis and inflammation after unilateral ureteral obstruction (UUO) and kidney ischemia/reperfusion injury (IRI) independent of blood pressure (BP) changes [25,31]
We previously demonstrated that inhibition of α2-adrenergic receptors (AR) prevents interstitial fibrogenesis after IRI, as indicated by reduced TGF-β1 production, Smad3 phosphorylation, α-SMA expression, and collagen deposition [31]
Summary
Acute kidney injury (AKI) is associated with increased mortality and risk of development of chronic kidney disease (CKD) in the long term [1,2]. Despite being a major unmet medical need, current efforts are restricted to the control of blood pressure (BP) and optimization of renin–angiotensin–aldosterone system (RAAS) blockade These therapies, at best, may reduce proteinuria, a surrogate marker of renal disease, but they only partially reduce progression of CKD [5]. Increased renal afferent activity directly influences sympathetic outflow to the kidneys via efferent nerves [6–8]. Despite the recognition of the renal sympathetic nerve system as the effector of renal dysfunction in CKD, its role in the progression and development of CKD has not been well defined. RDNx performed surgically or chemically reduces sympathetic nerve activity and has been shown to reduce BP, improve renal function, and attenuate the progression of CKD in experimental models and humans of hypertension and CKD [23–30]. We review the progress in our understanding of the molecular mechanisms of NE and ARs signaling in AKI, AKI to CKD transition and CKD
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