Adenosine receptors as emerging therapeutic targets for diabetic kidney disease

Abstract

Diabetic kidney disease (DKD) is now a pandemic worldwide, and novel therapeutic options are urgently required. Adenosine, an adenosine triphosphate metabolite, plays a role in kidney homeostasis through interacting with four types of adenosine receptors (ARs): A1AR, A2AAR, A2BAR, and A3AR. Increasing evidence highlights the role of adenosine and ARs in the development and progression of DKD: 1) increased adenosine in the plasma and urine of diabetics with kidney injury, 2) increased expression of each of the ARs in diabetic kidneys, 3) the protective effect of coffee, a commonly ingested nonselective AR antagonist, on DKD, and 4) the protective effect of AR modulators in experimental DKD models. We propose AR modulators as a new therapeutic option to treat DKD. Detailed mechanistic studies on the pharmacology of AR modulators will help us to develop effective first-in-class AR modulators against DKD.

Keywords: Adenosine; Diabetic kidney disease; Fibrosis; Purinergic P1 receptor agonists; Purinergic P1 receptor antagonists; Purinergic P1 receptors.

Figure 1.. Adenosine: formation and metabolism.

Intracellular adenosine is generated from SAH hydrolase or 5’NTD and is degraded by ADA and AK. Extracellular adenosine is generated by CD73 and converted to inosine by ADA. ENTs allow adenosine flux through the cell membrane depending on gradient concentration. ADA, adenosine deaminase; AK, adenosine kinase; AMP, adenosine monophosphate; ATP, adenosine triphosphate; ENT, equilibrative nucleoside transporter; SAH, S-adenosylhomocysteine; 5’NTD, 5’-nucleotidase.

Figure 2.. Signaling cascade of each AR.

AR, adenosine receptor; cAMP, cyclic adenosine monophosphate; CREB, cAMP-response element-binding protein; DAG, diacylglycerol; Epac, exchange proteins activated by cAMP; ERK, extracellular signal-regulated protein kinase; GSK-3β, glycogen synthase kinase 3 beta; IP₃, inositol trisphosphate; JNK, c-Jun N-terminal kinase; MAPK, mitogen-activated protein kinase; NO, nitric oxide; PI3K, phosphatidylinositol 4,5-bisphosphate; PLD, phospholipase D.

Figure 3.. Distribution of ARs in the kidney.

(A) Summary of each AR expressed in the nephron. (B) Expression of each AR in healthy mouse kidney delineated by single-cell transcriptomic analysis (https://susztaklab.com). A-IC, alpha intercalated cell; ALOH, ascending loop of Henle; AR, adenosine receptor; B-IC, beta intercalated cell; CD-PC, collecting duct principal cell; CD-Trans, CD transient cell; CNT, connecting tubule; DC 11b+, CD11b+ dendritic cell; DCT, distal convoluted tubule; DLOH, descending loop of Henle; Endo, endothelial; Fib, fibroblast; GEC, glomerular endothelial cells; Granul, granulocyte; LOH, loop of Henle; Macro, macrophage; Neutro, neutrophil; NK, natural killer cell; pDC, plasmacytoid DC; Podo, podocyte; PT, proximal tubule; Tgd, gamma delta T cell; Treg, regulatory T cell.

Figure 4.. Urinary excretion of adenosine and renal expression of ARs in diabetic patients.

(A) Urinary excretion of adenosine from normal (n = 10), normoalbuminuria (n = 10), microalbuminuria (n = 10), and overt proteinuria (n = 10) were measured. (B) Immunostaining of ARs was performed from minor glomerulopathy, minimal change disease, and DKD. Original magnification ×400. The data are presented as the mean ± standard error of mean. AR, adenosine receptor; Cr, creatinine; DKD, diabetic kidney disease. ^**p < 0.01, ^***p < 0.01 vs. control; ^†p < 0.05 vs. normoalbuminuria.

Figure 5.. The expression of ARs in diabetic kidney.

(A, B) Messenger RNA (mRNA) expressions of ARs were obtained from kidney homogenate of STZ-induced diabetic mice (12 weeks after STZ injury) and 20-week-old db/db mice. (C) Microarray analyses of human kidney biopsy data were provided in the Nephroseq database (nephroseq.org). The data are presented as the mean ± standard error of mean. AR, adenosine receptor; ERCB, European Renal cDNA Bank; STZ, streptozotocin. ^*p < 0.05 vs. control, db/m, normal.

Figure 6.. The role of ARs in diabetic kidney disease.

Each AR has either stimulatory (red dashed arrows) or inhibitory (blue solid inhibitory lines) effects on inflammation, fibrosis, oxidative stress, hyperglycemia, UAE, and GFR in diabetic kidneys. AR, adenosine receptor; GFR, glomerular filtration rate; UAE, urinary albumin excretion.