Dataset Information

Arctigenin attenuates diabetic kidney disease through the activation of PP2A in podocytes

ABSTRACT: Arctigenin (ATG) is a major component of Fructus Arctii, which as a traditional herbal remedy reduced proteinuria in diabetic patients. However, whether ATG specifically provided renoprotection in DKD was not known. Here we report that ATG administration is sufficient to attenuate proteinuria and podocyte injury in mouse models of diabetes. Transcriptomic analysis of diabetic mouse glomeruli showed that cell adhesion and inflammation are two key pathways affected by ATG treatment, and mass spectrometry analysis identified protein phosphatase 2A (PP2A) as one of the top ATG-interacting proteins in renal cells. Enhanced PP2A activity by ATG reduces p65 NF-κB-mediated inflammatory response and high glucose-induced migration in cultured podocytes via its interaction with Drebrin-1. Importantly, podocyte-specific Pp2a deletion in mice exacerbates DKD injury and abrogates the ATG-mediated renoprotection. Collectively, our results clearly demonstrate a renoprotective mechanism of ATG via PP2A activation and establish PP2A as a potential target for DKD progression.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Early Embryonic Cell

SUBMITTER: Tong Liu

LAB HEAD: John Cijiang He

PROVIDER: PXD014976 | Pride | 2019-11-08

REPOSITORIES: Pride

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			Action	DRS
	LiuRuijie_sample_ATG.mzid.gz	Mzid
	LiuRuijie_sample_ATG.mzid_LiuRuijie_sample_ATG.MGF	Mzid
	LiuRuijie_sample_ATG.mzid_LiuRuijie_sample_ATG.pride.mgf.gz	Mzid
	LiuRuijie_sample_ATG.pride.mztab.gz	Mztab
	LiuRuijie_sample_ATG.raw	Raw

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Arctigenin attenuates diabetic kidney disease through the activation of PP2A in podocytes.

Zhong Yifei Y Lee Kyung K Deng Yueyi Y Ma Yueming Y Chen Yiping Y Li Xueling X Wei Chengguo C Yang Shumin S Wang Tianming T Wong Nicholas J NJ Muwonge Alecia N AN Azeloglu Evren U EU Zhang Weijia W Das Bhaskar B He John Cijiang JC Liu Ruijie R

Nature communications 20191004 1

Arctigenin (ATG) is a major component of Fructus Arctii, a traditional herbal remedy that reduced proteinuria in diabetic patients. However, whether ATG specifically provides renoprotection in DKD is not known. Here we report that ATG administration is sufficient to attenuate proteinuria and podocyte injury in mouse models of diabetes. Transcriptomic analysis of diabetic mouse glomeruli showed that cell adhesion and inflammation are two key pathways affected by ATG treatment, and mass spectromet ...[more]

PMID: 31586053

Similar Datasets

Project description:Background: Diabetic kidney disease (DKD) is the leading cause of end-stage renal disease worldwide with limited treatment options. The intricate pathogenesis of dysregulated lipid metabolism leading to the development of DKD remains obscure. Lipophagy, which refers to the autophagic degradation of intracellular lipid droplets, has been found to be impaired in DKD, resulting in renal tubule dysfunction and ectopic lipid deposition (ELD). The lipotoxity in renal tubules is closely related to the pathogenesis of DKD. Therefore, it is crucial to develop effective and safe agents that can restore autophagic flux and lipophagy in renal tubules for potential preventive interventions. Purpose: This study seeks to investigate the preventive effect of sodium butyrate (NaB) on ELD in the progression of DKD and elucidate the underlying mechanisms involved.Methods: The beneficial effects of NaB were investigated in glucolipotoxicity (GLT)-stimulated HK-2 cells and the streptozotocin (STZ) injection combined with a high-fat diet induced DKD model mice. Additionally, we managed to silence transcription factor EB (TFEB) in HK-2 cells and establish the renal specific silence model by retrograde ureteral infusion of AAV9-shTFEB in mice. We investigated the expression profile of RNAs in HK-2 cells through. The mechanism of NaB is demonstrated by RNA sequencing (RNA-seq), pulldown MS assay, SPR experiments etc.Results: Our findings revealed that serum butyrate level is reduced in DKD patients and is statistically correlated with urinary protein excretion and eGFR. Sodium butyrate (NaB) dose-dependently improved lipid deposition in HK-2 cells and renal tubular epithelial cells of DKD model mice. This effect may be attributed to the promotion of TFEB dephosphorylation, as NaB can directly interact with PPP2R1A to activate PP2A phosphorylation activity. Therefore, NaB may play a role in improving renal lipid deposition in DKD through the PP2A-TFEB pathway. Conclusion: NaB acts as a PP2A-TFEB axis activator that restores lipophagy to ameliorate ELD and renal dysfunction in DKD.