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  3. Diminished nuclear-localized β-adrenoceptor signalling activates YAP to promote kidney fibrosis in diabetic nephropathy

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

  • Br J Pharmacol. 2024 Oct 2. doi: 10.1111/bph.17347.
Wenjing Xiang 1,  Lei Li 2,  Manman Qin 3,  Lei Li 1,  Hualong Yu 1,  Fangyuan Wang 1,  Siyuan Ni 1,  Ao Shen 4,  Haocheng Lu 1,  Haibo Ni 5,  Ying Wang 1 6
Affiliations

Affiliations

  • 1 Department of Pharmacology, School of Medicine, Southern University of Science and Technology, Shenzhen, China.
  • 2 School of Public Health, Xi'an Jiao Tong University, Xi'an, China.
  • 3 Mass Spectrometry Laboratory for BioSample analysis, Jiangxi University of Chinese Medicine, Nanchang, China.
  • 4 Guangzhou Municipal and Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology, The State & NMPA Key Laboratory of Respiratory Disease School of Pharmaceutical Sciences & The Fifth Affiliated Hospital Guangzhou Medical University, Guangzhou, China.
  • 5 Department of Pharmacology, University of California at Davis, Davis, California, USA.
  • 6 Joint Laboratory of Guangdong-Hong Kong Universities for Vascular Homeostasis and Diseases, Shenzhen, China.
PMID: 39359016 DOI: 10.1111/bph.17347
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 β1-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.

Keywords

YAP; diabetic nephropathy; fibrosis; mesangial cells; phosphodiesterase; signalling microdomain; β1adrenoceptor.

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