β2-Adrenergic receptor agonism as a therapeutic strategy for kidney disease

Abstract

Approximately 14% of the general population suffer from chronic kidney disease that can lead to acute kidney injury (AKI), a condition with up to 50% mortality for which there is no effective treatment. Hypertension, diabetes, and cardiovascular disease are the main comorbidities, and more than 660,000 Americans have kidney failure. β₂-Adrenergic receptors (β₂ARs) have been extensively studied in association with lung and cardiovascular disease, but with limited scope in kidney and renal diseases. β₂ARs are expressed in multiple parts of the kidney including proximal and distal convoluted tubules, glomeruli, and podocytes. Classical and noncanonical β₂AR signaling pathways interface with other intracellular mechanisms in the kidney to regulate important cellular functions including renal blood flow, electrolyte balance and salt handling, and tubular function that in turn exert control over critical physiology and pathology such as blood pressure and inflammatory responses. Nephroprotection through activation of β₂ARs has surfaced as a promising field of investigation; however, there is limited data on the pharmacology and potential side effects of renal β₂AR modulation. Here, we provide updates on some of the major areas of preclinical kidney research involving β₂AR signaling that have advanced to describe molecular pathways and identify potential drug targets some of which are currently under clinical development for the treatment of kidney-related diseases.

Keywords: adrenergic; electrolyte; fluid; kidney; β2AR.

Figure 1.

Role of β₂ adrenergic receptor (β₂AR) signaling in mitochondrial biogenesis. β₂AR stimulation by formoterol leads to mitochondrial biogenesis via a myriad of pathways demonstrated in several animal models and primary renal cells (left). This is also achieved downstream in the β₂-adrenergic signaling pathway by the adenylate cyclase activator, forskolin as demonstrated (right). ADR: adriamycin; cGMP, guanosine 3′,5′-cyclic monophosphate; CREB, cAMP response element-binding protein; Drp-1, dynamin-related protein 1; ETC, electron transport chain; IR, ischemia reperfusion; KIM-1, kidney injury molecule-1; Mfn1, mitofusin 1; mtDNA #, mitochondrial DNA copy number; OCR, oxygen consumption rate; PAN, puromycin-aminonucleoside; PGC1-α, peroxisome proliferator-activated receptor γ coactivator 1-α; PI3K, phosphatidylinositol 3′-kinase; PKA, protein kinase A; PKG, protein kinase G; RPTCs, renal proximal tubular cells; sGC, soluble guanylyl cyclase.

Figure 2.

Effects of β₂ adrenergic receptor (β₂AR) signaling on salt handling in renal tubules. β₂AR signaling increases renal sodium reabsorption by: 1) Increasing the activity of Na-K-ATPase pump in proximal tubular epithelial cells in a protein kinase C (PKC)-dependent manner (left); 2) Blocking the inhibition of Na-Cl Co-transporter (NCC) by with-no-lysine (K) kinase 4 (WNK4) in distal renal tubular cells through a adenosine 3′,5′-cyclic monophosphate (cAMP)-protein kinase A (PKA)-mediated pathway (right). Image is from Servier Medical Art images (https://smart.servier.com).

Figure 3.

Role of β₂ adrenergic receptor (β₂AR) signaling in renal inflammation. β₂AR agonism by various agents is shown to reduce the proinflammatory response and renal apoptosis and fibrosis in ex vivo and in vitro models (left). β₂AR inhibition in lipopolysaccharide (LPS)-induced sepsis in rats increases renal inflammation by inducing cluster of differentiation 14 (CD14), Toll-like receptor 4 (TLR4), and tumor necrosis factor α (TNFα) mediated by suppressed adenosine 3′,5′-cyclic monophosphate (cAMP)/ protein kinase A (PKA) activity (middle). Overexpression of β₂ARs via gene delivery improves renal function [increased creatinine clearance and glomerular filtration rate (GFR)] in rat models of endotoxin-induced acute renal failure (ARF) and of systemic inflammation (right). ACHN, adenocarcinoma renal cell line; ANG II, angiotensin II; MAPK, mitogen-activated protein kinase; NF-kB, nuclear factor κ B; NO, nitric oxide; PKC, protein kinase C; Stx2, Shiga toxin-2; ZDF, Zucker diabetic fatty.

Figure 4.

Role of β₂ adrenergic receptor (β₂AR) signaling in heart-brain-kidney cross-talk during myocardial adaptation to pressure overload. Upon induction of cardiac pressure overload in a mouse model of transaortic constriction, sympathetic nerves are activated and stimulate collecting duct (CD) epithelial cells in the kidney via a β₂AR-dependent pathway. Activated duct cells respond by incorporating renal macrophages that in turn cause endothelial cell (EC) activation. Activated ECs release colony-stimulating factor 2 (CSF2) and stimulate cardiac Ly6C^lo macrophages to produce the cardioprotective mediator amphiregulin. Image is from Servier Medical Art images (https://smart.servier.com).

Figure 5.

Renal β₂ adrenergic receptor (β₂AR) in clinical studies. Summary of clinical studies investigating β₂AR-related effects renal disease. ccRCC, clear cell renal cell carcinoma; CRE, creatinine; CRS, cardiorenal syndrome; ESRD, end-stage renal disease; GFR, glomerular filtration rate; HF, heart failure.