Sodium glucose transporter 2 inhibition maintains kidney antibacterial response by decreasing complement C1q

Glucose promotes bacterial growth. Sodium-glucose transporter 2 inhibition (SGLT2i), which prevents glucose recovery from the urine, is standard therapy in chronic kidney diseases. However, kidney bacterial infection rates did not increase. Here, we investigated possible underlying mechanisms contributing to this effect.

We studied patients and a mouse model of pyelonephritis with and without inhibition of urinary glucose reabsorption using primary murine and human cell culture. Analysis involved a combination of histology, flow cytometry and gene expression analysis.

Clinical urinary tract infection (UTI) severity and the murine pyelonephritis model reflect a sustained kidney antibacterial response during SGLT2i. A gene expression screen revealed decreased complement C1q expression in pyelonephritic kidneys with SGLT2i along with decreased serum C1q protein. C1q and SGLT2 colocalized in proximal tubules. SGLT2i diminished C1q and modulated surface markers including tyrosine kinase MERTK on the same myeloid cell subset in vivo. In human epithelial cell and peripheral blood mononuclear cell coculture, SGLT2i decreased C1q and MERTK. C1q upregulated MERTK, impaired tumor necrosis factor-α and interleukin-1β secretion and monocyte-mediated neutrophil chemotaxis. Baseline C1q levels were significantly higher in plasma of UK Biobank participants who developed UTI than in propensity score matched control participants.

Our study delineates regulation of C1q and subsequent monocyte antibacterial functions as a potential mechanism of UTI response regulated by SGLT2i. C1q should also be explored as a possible pathogenic factor in chronic kidney damage amenable to SGLT2i.