Diminished nuclear‐localized β‐adrenoceptor signalling activates YAP to promote kidney fibrosis in diabetic nephropathy

Abstract Background and Purpose Diabetic nephropathy (DN) is a leading cause of chronic kidney disease (CKD), which is characterized by mesangial matrix expansion that involves dysfunctional mesangial cells (MCs). However, the underlying mechanisms remain unclear. This study aims to delineate the spatiotemporal contribution of adrenergic signalling in diabetic kidney fibrosis to reveal potential therapeutic targets. Experimental Approach A model of diabetic nephropathy was induced by in db/db mice. Gene expression in kidneys was profiled by RNA‐seq analyses, western blot and immunostaining. Subcellular‐localized fluorescence resonance energy transfer (FRET) biosensors determined adrenergic signalling microdomains in MCs. Effects of oral rolipram, a phosphodiesterase 4 (PDE4) inhibitor, on the model were measured. Key Results Our model exhibited impaired kidney function with elevated expression of adrenergic and fibrotic genes, including Adrb1, PDEs, Acta2 and Tgfβ . RNA‐seq analysis revealed that MCs with dysregulated YAP pathway were crucial to the extracellular matrix secretion in kidneys from diabetic nephropathy patients. In cultured MCs, TGF‐ β promoted profibrotic gene transcription, which was regulated by nuclear‐localized β ‐adrenoceptor signalling. Mechanistically, TGF‐ β treatment diminished nuclear‐specific cAMP signalling in MCs and reduced PKA‐dependent phosphorylation of YAP, leading to its activation. In parallel, db/db mouse kidneys showed increased expressions of PDE4B and PDE4D. Treatment with oral rolipram alleviated kidney fibrosis in db/db mice. Conclusion and Implications Diabetic nephropathy impaired nuclear‐localized β 1 ‐adrenoceptor‐cAMP signalling microdomain through upregulating PDE4 expression, promoting fibrosis in MCs via PKA dephosphorylation‐dependent YAP activation. Our results suggest PDE4 inhibition as a promising strategy for alleviating kidney fibrosis in diabetic nephropathy.