Intestinal Bacterial Translocation Contributes to Diabetic Kidney Disease

Hoang Thuy Linh; Yasunori Iwata; Yasuko Senda; Yukiko Sakai-Takemori; Yusuke Nakade; Megumi Oshima; Shiori Nakagawa-Yoneda; Hisayuki Ogura; Koichi Sato; Taichiro Minami; Shinji Kitajima; Tadashi Toyama; Yuta Yamamura; Taro Miyagawa; Akinori Hara; Miho Shimizu; Kengo Furuichi; Norihiko Sakai; Hiroyuki Yamada; Katsuhiko Asanuma; Kouji Matsushima; Takashi Wada

doi:10.1681/ASN.2021060843

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Significance Statement

Intestinal barrier dysfunction—a “leaky gut”—reportedly contributes to pathological processes in some diseases. In a mouse model, the authors induced diabetic kidney disease, leading to impaired intestinal integrity and inflammation, with IL-17 upregulation. This allowed intestine-derived Klebsiella oxytoca and elevated IL-17 to translocate to the circulation and kidneys, then accelerate kidney injury, especially in diabetic knockout mice lacking mitochondrial antiviral signaling protein (MAVS). Stimulation of tubular epithelial cells with K. oxytoca activated the MAVS pathway and phosphorylation of Stat3 and ERK1/2, leading to production of kidney injury molecule-1 (KIM-1). Systemic MAVS is renoprotective in diabetic mice by an intestinal protective role and the dominant inhibitory effects on suppressing KIM-1 expression under K. oxytoca supernatant or IL-17 stimulation. Controlling intestinal homeostasis may offer a therapeutic strategy in 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 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.

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