The role of gut HIF-1 signaling in kidney-gut crosstalk in kidney IRI

• Grant number: 21/06748-3
• Support type: Regular Research Grants
• Duration: December 01, 2021 - November 30, 2023
• Field of knowledge: Health Sciences - Medicine - Medical Clinics
• Cooperation agreement: National Research Foundation of Korea (NRF)
• Principal researcher: Niels Olsen Saraiva Câmara
• Grantee: Niels Olsen Saraiva Câmara
• Principal researcher abroad: Sang Kyung Jo
• Institution abroad: Korea University Anam Hospital, South Korea
• Home Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Assoc. researchers: Myung-Gyu Kim ; Orestes Foresto Neto

Abstract

Recent studies from our labs have shown an unique bidirectional relationship between the kidney and gut in mouse model of kidney injury. We found that kidney injury profoundly altered intestinal microbiota with barrier disruption, bacterial translocation, metabolic, immune dysfunction and also that this dysbiosis subsequently worsened kidney injury by augmenting inflammation. Our korean colleagues have showed that the depletion of microbiota exerts renoprotective effect via barrier protection and immune modulation, we suggested that targeting the intestine might represent a novel strategy for the prevention and treatment of acute kidney injury (AKI). In addition to serving as the habitus for trillions of microorganisms and the single largest organ of the immune system, the gastrointestinal (GI) tract is also characterized by unique oxygenation profiles from the anaerobic lumen, home for anaerobic gut commensals to highly vascularized submucosal layer. Therefore, intestinal epithelial cells have evolved to adapt to this normal physiological hypoxic environment. Hypoxia inducible factor (HIF) is well known as a master regulator of oxygen homeostasis and not only facilitate oxygen delivery but also help cells adapt to oxygen deprivation states. Several reports demonstrated that the lack of intestinal epithelial HIF-1a might lead to barrier disruption, aberrant mucosal lymphocyte activation leading to mucosal inflammation. Given that mucosal inflammation, together with barrier disruption could lead to potentiation of systemic/kidney inflammation, intestinal HIF-1a signaling might be an interesting molecular target in AKI. Moreover, HIF1a expression in renal cells, such as podocytes and tubular cells, can work as sensor of microenvironment modifications and initiate an inflammatory response, by inducing cellular reprograming, after injury, that could systemically alter the gut homeostasis. This crosstalk between intestine and kidney would have a common path, HIF1a. Therefore, based on these recent data addressing the important role of intestinal HIF-1a in maintaining the normal intestinal microenvironment, we hypothesized that differential regulation of intestinal HIF-1a after kidney IRI might have certain effects not only on the microbial structure, barrier disruption, subsequent bacterial translocation, and aberrant mucosal immune response, but also on kidney inflammation and injury. (AU)