Trimethylamine N-Oxide Exacerbates Renal Inflammation and Fibrosis in Rats With Diabetic Kidney Disease.

Qing Fang,Jinfeng Liu,Wenhui Liu,Xinyi Huang,Na Liu,Lulu Chen,Dongsheng Ouyang,Binjie Zheng,Zhenyu Li,Xiangchang Zeng

doi:10.3389/fphys.2021.682482

Abstract

The gut microbiota plays a pivotal role in the onset and development of diabetes and its complications. Trimethylamine N-oxide (TMAO), a gut microbiota-dependent metabolite of certain nutrients, is associated with type 2 diabetes and its complications. Diabetic kidney disease (DKD) is one of the most serious microvascular complications. However, whether TMAO accelerates the development of DKD remains unclear. We tested the hypothesis that TMAO accelerates the development of DKD. A high-fat diet/low-dose streptozotocin-induced diabetes rat model was established, with or without TMAO in the rats’ drinking water. Compared to the normal rats, the DKD rats showed significantly higher plasma TMAO levels at the end of the study. TMAO treatment not only exacerbated the kidney dysfunction of the DKD rats, but also renal fibrosis. Furthermore, TMAO treatment activated the nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3 (NLRP3) inflammasome and resulted in the release of interleukin (IL)-1β and IL-18 to accelerate renal inflammation. These results suggested that TMAO aggravated renal inflammation and fibrosis in the DKD rats, which provides a new perspective to understand the pathogenesis of DKD and a potential novel target for preventing the progression of DKD.

Highlights

Diabetic kidney disease (DKD), or diabetic nephropathy, is one of the most fatal complications of diabetes mellitus, and it is the most prevailing element of end-stage renal disease (Cansby et al, 2020)
Compared to the rats in the CON group, the body weights of the rats in the DKD group were decreased from the fifth week and the fasting blood glucose levels of the rats in the DKD group were higher from the sixth week
The major findings of this study were: (1) the rats with DKD had increased circulating Trimethylamine N-oxide (TMAO) levels; (2) the circulating TMAO levels of the CON + TMAO rats administered TMAO for 12 weeks were almost the same as those of the DKD rats; (3) TMAO administration in the DKD group decreased the body weights and increased the fasting blood glucose levels of the rats, while it had no effect on TG and Total cholesterol (TC) levels; and (4) TMAO facilitated tubulointerstitial injury and renal fibrosis, and it activated the NLRP3 inflammasome to exacerbate renal inflammation

Summary

Introduction

Diabetic kidney disease (DKD), or diabetic nephropathy, is one of the most fatal complications of diabetes mellitus, and it is the most prevailing element of end-stage renal disease (Cansby et al, 2020). Metabolic changes caused by diabetes lead to proteinuria, progressive mesangial expansion, glomerular basement membrane thickening, tubulointerstitial fibrosis, and impaired renal function (Alicic et al, 2017). The underlying pathogenesis of DKD is complex and involves many different pathways. Studies have shown that several factors are major contributors in the pathophysiology of DKD, including oxidative stress, inflammation, overexpression of transforming growth factor-β1 (TGF-β1), and other metabolic alterations Despite improved prognosis over the years, the pathogenesis of DKD has not been fully elucidated. Understanding the mechanism of DKD will enable prevention and early intervention, which will result in better outcomes

Methods

Results

Conclusion