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Updated: Oct 1, 2025
Comparative Proteomic Analysis of Whole Kidney, Medulla, and Cortical Tubules in Diabetic Pathogenesis of Kidney Injury in Mice
Published on: May 2, 2025
Intestinal Bacterial Translocation Contributes to Diabetic Kidney Disease
Hoang Thuy Linh1, Yasunori Iwata1,2, Yasuko Senda2
1Department of Nephrology and Laboratory Medicine, Kanazawa University, Kanazawa, Japan.
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 pathologic 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, LPS 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.
Insights
Impaired intestinal barrier function due to disrupted Mitochondrial antiviral signaling protein (MAVS) signaling exacerbates diabetic kidney disease. Restoring intestinal homeostasis may offer new therapeutic strategies for kidney protection.
Area of Science:
- Immunology
- Nephrology
- Gastroenterology
Background:
- Intestinal barrier dysfunction, or "leaky gut," is implicated in various diseases, including kidney disorders.
- Mitochondrial antiviral signaling protein (MAVS) is crucial for maintaining intestinal integrity as part of innate immunity.
- The role of MAVS signaling in intestinal homeostasis disruption and its impact on diabetic kidney disease (DKD) remain largely unknown.
Purpose of the Study:
- To investigate the contribution of intestinal barrier impairment to kidney injury in a mouse model of diabetic kidney disease.
- To elucidate the role of Mitochondrial antiviral signaling protein (MAVS) in the pathogenesis of diabetic kidney disease.
Main Methods:
- Diabetic kidney disease was induced in wild-type and MAVS knockout mice via unilateral nephrectomy and streptozotocin.
- Kidney and intestinal injuries, along with bacterial translocation, were assessed.
- Cellular responses to bacterial components and cytokines were analyzed in vitro.
Main Results:
- MAVS knockout diabetic mice exhibited more severe kidney injuries and impaired intestinal integrity.
- Intestine-derived *Klebsiella oxytoca* and elevated IL-17 were found in circulation and kidneys, particularly in MAVS knockout mice.
- MAVS signaling modulated tubular epithelial cell responses to *K. oxytoca* and IL-17, influencing kidney injury molecule-1 (KIM-1) production; anti-IL-17 treatment showed protective effects.
Conclusions:
- Disrupted MAVS signaling in both the kidney and intestine contributes to DKD progression by impairing homeostasis.
- Targeting intestinal homeostasis presents a potential novel therapeutic avenue for managing diabetic kidney disease.
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