A-306989, an inhibitor of adenosine kinase, is renoprotective in rodent models of podocyte, basement membrane, and obstructive injury.
Adenosine (ADO) is an important regulatory purine nucleoside that accumulates at sites of inflammation and tissue injury including in diseases associated with renal pathology. Endogenous levels of ADO may be increased by inhibiting the ADO-metabolizing enzyme, ADO kinase (AK). AK inhibitors have demonstrated protection in rodent models of diabetic nephropathy. To further investigate AK inhibition as a potential mechanism for renal protection, A-306989, a potent non-nucleoside AK inhibitor, was examined in both in vitro and in vivo assays of renal injury. A-306989 prevented podocyte damage (disruption of actin cytoskeleton) and increased podocyte survival following puromycin aminonucleoside (PAN) application in both mouse and human conditionally immortalized podocytes. Prophylactic oral administration of A-306989 (1.5, 5 and 15mg/kg) reduced proteinuria in a dose-dependent manner and repressed pro-inflammatory/fibrotic gene up-regulation; A-306989 was also efficacious when administered two days following the PAN-insult. A-306989 (10 and 30mg/kg) also significantly reduced proteinuria and macrophage infiltration in a rat model of glomerulonephritis. Finally, A-306989 (15 and 50mg/kg) reduced the expression levels of pro-inflammatory/fibrotic genes, and reduced macrophage infiltration (50mg/kg), but did not affect the deposition of interstitial collagen in fibrotic kidneys from mice with unilateral ureter obstruction. A-306989 also had beneficial actions on "quality of life" measures including improving body weight loss. Thus, these data indicate that enhancement of endogenous ADO levels by A-306989 can positively modulate renal pathology and mimic some of the previously reported beneficial actions of ADO A2A receptor agonists.
Renal Research, Research and Development, AbbVie, 1 North Waukegan Road, North Chicago, IL 60064, USA. Electronic address: chang.z.zhu@abbvie.com.
Chang Z
CZ
Zhu
Renal Research, Research and Development, AbbVie, 1 North Waukegan Road, North Chicago, IL 60064, USA.
Sujatha
S
Gopalakrishnan
Renal Research, Research and Development, AbbVie, 1 North Waukegan Road, North Chicago, IL 60064, USA.
Kelly
K
Doyle
Renal Research, Research and Development, AbbVie, 1 North Waukegan Road, North Chicago, IL 60064, USA.
Arthur L
AL
Nikkel
Renal Research, Research and Development, AbbVie, 1 North Waukegan Road, North Chicago, IL 60064, USA.
Lauren
L
Olson
Renal Research, Research and Development, AbbVie, 1 North Waukegan Road, North Chicago, IL 60064, USA.
Vivek C
VC
Abraham
Renal Research, Research and Development, AbbVie, 1 North Waukegan Road, North Chicago, IL 60064, USA.
Laura
L
Leys
Renal Research, Research and Development, AbbVie, 1 North Waukegan Road, North Chicago, IL 60064, USA.
Deborah
D
Widomski
Renal Research, Research and Development, AbbVie, 1 North Waukegan Road, North Chicago, IL 60064, USA.
Katherine
K
Salte
Renal Research, Research and Development, AbbVie, 1 North Waukegan Road, North Chicago, IL 60064, USA.
Brent
B
Putman
Renal Research, Research and Development, AbbVie, 1 North Waukegan Road, North Chicago, IL 60064, USA.
Steve
S
Pratt
Renal Research, Research and Development, AbbVie, 1 North Waukegan Road, North Chicago, IL 60064, USA.
Ji
J
Ma
Renal Research, Research and Development, AbbVie, 1 North Waukegan Road, North Chicago, IL 60064, USA.
Zhi
Z
Su
Renal Research, Research and Development, AbbVie, 1 North Waukegan Road, North Chicago, IL 60064, USA.
Murali
M
Gopalakrishnan
Renal Research, Research and Development, AbbVie, 1 North Waukegan Road, North Chicago, IL 60064, USA.
Chih-Hung
CH
Lee
Renal Research, Research and Development, AbbVie, 1 North Waukegan Road, North Chicago, IL 60064, USA.
Steve P
SP
McGaraughty
D000248:Adenosine Kinase / Q000037:antagonists & inhibitors*; D000818:Animals; D001485:Basement Membrane / Q000000981:diagnostic imaging*; D019610:Cytoprotection / Q000187:drug effects*; D005355:Fibrosis; D007668:Kidney / Q000166:cytology* / Q000187:drug effects / Q000293:injuries* / Q000473:pathology; D008297:Male; D051379:Mice; D050199:Podocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011692:Puromycin Aminonucleoside / Q000633:toxicity; D051381:Rats
D047428:Protein Kinase Inhibitors; D011692:Puromycin Aminonucleoside; D000248:Adenosine Kinase
A-306989; Adenosine kinase inhibitor; Animal model; Cyclosporine (PubChem CID: 5284373); Mizoribine (PubChem CID: 104762); Renoprotective