Intestinal Bacterial Translocation Contributes to Diabetic Kidney Disease

Abstract

Background In recent years, many studies have focused on the intestinal environment to elucidate pathogenesis of various diseases, including kidney diseases. Impairment of the intestinal barrier function, the "leaky gut," reportedly contributes to pathological processes in some disorders. Mitochondrial antiviral signaling protein (MAVS), a component of innate immunity, maintains intestinal integrity. The effects of disrupted intestinal homeostasis associated with MAVS signaling in diabetic kidney disease remains unclear. Methods To evaluate the contribution of intestinal barrier impairment to kidney injury under diabetic conditions, we induced diabetic kidney disease in wild-type and MAVS knockout mice through unilateral nephrectomy and streptozotocin treatment. We then assessed effects on the kidney, intestinal injuries, and bacterial translocation. Results MAVS knockout diabetic mice showed more severe glomerular and tubular injuries compared with wild-type diabetic mice. Owing to impaired intestinal integrity, the presence of intestine-derived Klebsiella oxytoca and elevated IL-17 were detected in the circulation and kidneys of diabetic mice, especially in diabetic MAVS knockout mice. Stimulation of tubular epithelial cells with K. oxytoca activated MAVS pathways and the phosphorylation of Stat3 and ERK1/2, leading to the production of kidney injury molecule-1 (KIM-1). Nevertheless, MAVS inhibition induced inflammation in the intestinal epithelial cells and KIM-1 production in tubular epithelial cells under K. oxytoca supernatant or IL-17 stimulation. Treatment with neutralizing anti-IL-17 antibody treatment had renoprotective effects. In contrast, lipopolysaccharide administration accelerated kidney injury in the murine diabetic kidney disease model. Conclusions Impaired MAVS signaling both in the kidney and intestine contributes to the disrupted homeostasis, leading to diabetic kidney disease progression. Controlling intestinal homeostasis may offer a novel therapeutic approach for this condition.

Identification of Oxidative Stress-Related Biomarkers in Diabetic Kidney Disease

“…Among them, the IL-17 signaling pathway and TNF signaling pathway are closely associated with the occurrence and development of diabetic nephropathy. IL-17 is a key cytokine secreted by CD4 + T cells [ 17 ]. In the high glucose state, the accumulation of AGEs increases the expression of IL-17 [ 18 , 19 ], and after binding to its receptor, it promotes IL-6, monocyte chemotactic protein (MCP-1), and regulates activation of monocytes.…”

Therapeutic mechanism and clinical application of Chinese herbal medicine against diabetic kidney disease

“…As an important component of innate immunity, mitochondrial antiviral signaling protein (MAVS) maintains intestinal integrity. DKD contributes to the impairment of MAVS signaling in the kidney and intestine thus leading to the disrupted homeostasis, indicating that maintaining intestinal homeostasis may functions a novel therapeutic approach for DKD treatment ( Linh et al, 2022 ).…”

Resistant Starch as a Dietary Intervention to Limit the Progression of Diabetic Kidney Disease

“…There are several factors which suggest this mechanism to exist in DKD. Firstly, intestinal barrier disruption has been observed in T2DM and CKD patients [ 62 ] as well as in mouse models of DKD [ 52 , 70 ]. Additionally, the gut microbiome changes observed in DKD are associated with a decline in intestinal barrier integrity [ 16 ].…”