The renal apical sodium‐dependent bile acid transporter expression rescue attenuates renal damage in diabetic nephropathy via farnesoid X receptor activation

Author:

Li Youmei12,Pang Shuguang134ORCID,Guo Honggang5,Yang Shuo4

Affiliation:

1. Department of Endocrinology, Jinan Central Hospital Shandong University Jinan China

2. Department of Endocrinology Changqing District People's Hospital Jinan China

3. Department of Endocrinology Central Hospital Affiliated to Shandong First Medical University Jinan China

4. Department of Clinical Medicine Weifang Medical College Weifang China

5. Laboratory of Experimental Animal and Safety Evaluation Hangzhou Medical College, Zhejiang Academy of Medical Sciences Hangzhou China

Abstract

AbstractAimBile acids (BA) function as signalling molecules regulating glucose‐lipid homeostasis and energy expenditure. However, the expression of the apical sodium‐dependent bile acid transporter (ASBT) in the kidney, responsible for renal BA reabsorption, is downregulated in patients with diabetic kidney disease (DKD). Using the db/db mouse model of DKD, this study aimed to investigate the effects of rescuing ASBT expression via adeno‐associated virus‐mediated delivery of ASBT (AAVASBT) on kidney protection.MethodsSix‐week‐old male db/db mice received an intraparenchymal injection of AAVASBT at a dose of 1 × 1011 viral genomes (vg)/animal and were subsequently fed a chow diet for 2 weeks. Male db/m mice served as controls. For drug treatment, daily intraperitoneal (i.p.) injections of the farnesoid X receptor (FXR) antagonist guggulsterone (GS, 10 mg/kg) were administered one day after initiating the experiment.ResultsAAVASBT treatment rescued renal ASBT expression and reduced the urinary BA output in db/db mice. AAVASBT treatment activated kidney mitochondrial biogenesis and ameliorated renal impairment associated with diabetes by activating FXR. In addition, the injection of FXR antagonist GS in DKD mice would reverse these beneficial effects by AAVASBT treatment.ConclusionOur work indicated that restoring renal ASBT expression slowed the course of DKD via activating FXR. FXR activation stimulates mitochondrial biogenesis while reducing renal oxidative stress and lipid build up, indicating FXR activation's crucial role in preventing DKD. These findings further suggest that the maintenance of renal BA reabsorption could be a viable treatment for DKD.

Publisher

Wiley

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