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Role of protein kinase A isoforms in healthy and diabetic kidneys

Affiliation
Institute of Pharmacy, Department of Pharmacology und Toxicology, University of Regensburg, Regensburg, Germany
Prüschenk, Sally;
Affiliation
Institute of Pharmacy, Department of Pharmacology und Toxicology, University of Regensburg, Regensburg, Germany
Harloff, Manuela;
Affiliation
School of Medicine, Department of Pharmacology, University of California San Diego, San Diego, United States of America
Ma, Yuliang;
Affiliation
School of Medicine, Department of Pharmacology, University of California San Diego, San Diego, United States of America
Taylor, Susan;
Affiliation
Institute of Pharmacy, Department of Pharmacology und Toxicology, University of Regensburg, Regensburg, Germany
Schlossmann, Jens

Diabetic nephropathy (DN) is a major universal problem caused by hyperglycaemia and might require dialysis or renal replacement. Still, the signaling events causing diabetic kidney disease and the effective treatment options are poorly understood. Alterations in the signaling of cyclic nucleotides and its regulated kinases might be involved in the development of this disease. Protein kinase A (PKA) signaling pathways are known to modulate extracellular matrix metabolism in diabetic kidneys. Multiple isoforms of PKA regulatory and catalytical subunits exist, leading to functional specificities of this kinase. As PKA was further described to exert antifibrotic effects, it might be important in prevention of fibrosis or DN. Localization of the specific PKA subunits as well as other signaling proteins involved in this pathway, however, still need to be explored comprehensively. The aim of our project is to get an overview about distribution pattern of different PKA subunits in various cell types of the kidney. Furthermore, amount of PKA expression in healthy and diabetic kidneys are compared. To achieve these goals, type 1 diabetes was induced with streptozotocin in wild-type (WT) and endothelial NOS knockout (eNOS-KO) mice for 12 weeks. Afterwards, kidneys were analyzed by immunohistochemistry and stained with specific antibodies for different PKA subunits and markers for specialized cell types of the kidney. Amount of PKA-Cα and PKA-Cβ expression was quantified and compared between healthy and diabetic kidneys. Our data thereby revealed that catalytic subunits of PKA show a different distribution pattern in specialized cell types of the kidney, but also a different intracellular localization. Furthermore, PKA-Cα appears to be the predominant isoform in a lot of cell types in the kidney. The amount of catalytic subunit expression also varies between healthy and diabetic kidneys. Therefore, PKA might play an important role in pathophysiology of DN and targeting the PKA signaling pathway could be a potential treatment approach.

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