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

Xiang, Wenjing1; Li, Lei1,2; Qin, Manman3; Yu, Hualong1; Wang, Fangyuan1; Ni, Siyuan1; Shen, Ao4,5; Lu, Haocheng1; Ni, Haibo6; Wang, Ying1,7

2024-10-01

10.1111/bph.17347

BRITISH JOURNAL OF PHARMACOLOGY   影响因子和分区

0007-1188

1476-5381

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 Tgf beta. 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-beta promoted profibrotic gene transcription, which was regulated by nuclear-localized beta-adrenoceptor signalling. Mechanistically, TGF-beta 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 beta(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.

diabetic nephropathy fibrosis mesangial cells phosphodiesterase signalling microdomain YAP beta(1)adrenoceptor

SCI

英语

第一 ; 通讯

null[K231141004] ; null[K23411108] ; null[82070406]

Pharmacology & Pharmacy

Pharmacology & Pharmacy

WOS:001326960300001

WILEY

Web of Science

1.Southern Univ Sci & Technol, Sch Med, Dept Pharmacol, Shenzhen, Peoples R China
2.Xi An Jiao Tong Univ, Sch Publ Hlth, Xian, Peoples R China
3.Jiangxi Univ Chinese Med, Mass Spectrometry Lab BioSample Anal, Nanchang, Peoples R China
4.Guangzhou Med Univ, State & NMPA Key Lab Resp Dis, Guangzhou Municipal & Guangdong Prov Key Lab Mol T, Sch Pharmaceut Sci, Guangzhou, Peoples R China
5.Guangzhou Med Univ, Affiliated Hosp 5, Guangzhou, Peoples R China
6.Univ Calif Davis, Dept Pharmacol, Davis, CA 95616 USA
7.Joint Lab Guangdong Hong Kong Univ Vasc Homeostasi, Shenzhen 518055, Guangdong, Peoples R China

Xiang, Wenjing,Li, Lei,Qin, Manman,et al. Diminished nuclear-localized β-adrenoceptor signalling activates YAP to promote kidney fibrosis in diabetic nephropathy[J]. BRITISH JOURNAL OF PHARMACOLOGY,2024.

Xiang, Wenjing.,Li, Lei.,Qin, Manman.,Yu, Hualong.,Wang, Fangyuan.,...&Wang, Ying.(2024).Diminished nuclear-localized β-adrenoceptor signalling activates YAP to promote kidney fibrosis in diabetic nephropathy.BRITISH JOURNAL OF PHARMACOLOGY.

Xiang, Wenjing,et al."Diminished nuclear-localized β-adrenoceptor signalling activates YAP to promote kidney fibrosis in diabetic nephropathy".BRITISH JOURNAL OF PHARMACOLOGY (2024).