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Diminished nuclear-localized β-adrenergic signaling activates YAP to
promote kidney fibrosis in diabetic nephropathy
Abstract
Background and purpose Diabetic nephropathy (DN) is a leading cause of
chronic kidney diseases (CKD) 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 signaling in diabetic
kidney fibrosis to reveal potential therapeutic target. Experimental
Approach Db/db mice were used to study DN. RNA sequence analyses,
western blot and immunostaining were conducted to profile gene
expression in kidneys. Subcellular-localized fluorescence resonance
energy transfer (FRET) biosensors determined adrenergic signaling
microdomains in MCs. Rolipram, a PDE4 inhibitor, was orally
administrated in db/db mice to test its impact on the kidney. Key
Results Db/db mice exhibited impaired kidney function with elevated
adrenergic and fibrotic gene expression, including ADRB1, PDEs, ACTA2,
and TGF-β. MCs with dysregulated YAP pathway played a pivotal role in
extracellular matrix secretion in DN. TGF-β up-regulated β1-adrenergic
receptors (β1ARs) and α-SMA in MCs. Diminished nuclear-specific cAMP
signaling in MCs by TGF-β triggered profibrotic gene transcription via
reducing PKA-dependent phosphorylation of YAP. The profibrotic formation
was partially alleviated by norepinephrine administration and prevented
by combined treatment of norepinephrine and rolipram. In db/db mice,
rolipram treatment alleviated kidney fibrosis and restored kidney
filtration function. Conclusion and Implications DN impairs
nuclear-localized β1AR-cAMP signaling microdomain through upregulating
PDE4 expression, promoting fibrosis in MCs via PKA
dephosphorylation-dependent YAP activation. Results suggest PDE4
inhibition as a promising strategy for alleviating kidney fibrosis in
DN.