Aminoglycoside-induced lipotoxicity and its reversal in kidney on chip
2Department of Cell and Developmental Biology, Silberman Institute of Life Sciences,, The Hebrew University of Jerusalem,, Israel
3TD, Tissue Dynamics,, Israel
4Department of Biological Chemistry, Institute of Chemistry,, the Hebrew University of Jerusalem, Jerusalem 91904, Israel, Israel
Aminoglycosides are an important class of antibiotics that play a critical role in the treatment of
life-threatening infections, but their use is limited by their toxicity. In fact, gentamicin causes
severe nephrotoxicity in 17% of hospitalized patients. The kidney proximal tubule is particularly
vulnerable to drug-induced nephrotoxicity due to its role in drug transport. In this work, we
developed a perfused vascularized model of human kidney tubuloids integrated with tissueembedded
microsensors that track the metabolic dynamics of aminoglycoside-induced renal
toxicity in real time. Our model shows that gentamicin disrupts proximal tubule polarity at
concentrations 20-fold below its TC50, leading to a 3.2-fold increase in glucose uptake, and reverse
TCA cycle flux culminating in a 40-fold increase in lipid accumulation. Blocking glucose
reabsorption using the SGLT2 inhibitor empagliflozin significantly reduced gentamicin toxicity
by 10-fold. These results demonstrate the utility of sensor-integrated kidney-on-chip platforms to
rapidly identify new metabolic mechanisms that may underly adverse drug reactions. The results
should improve our ability to modulate the toxicity of novel aminoglycosides.