Elevated Glucose Levels Cause Vital Epithelial Cells to Detach in Organoids

Stem cell researchers have identified inflammatory pathways that may play a key role in driving kidney damage in diabetic kidney disease (DKD), pointing to potential new approaches for protecting the kidneys. Using stem cell-derived kidney organoids, Benjamin Freedman and colleagues from the University of Washington, USA, found that exposure to high sugar levels triggered inflammation and disrupted the organoids' typical kidney tissue-like structure, causing individual kidney cells to detach. These changes were reminiscent of those observed in kidney biopsies and urine samples from patients with DKD. The research was published today in the peer-reviewed journal, Stem Cell Reports.

High sugar causes inflammation in these organoids even though they lack an immune system. This was unexpected and gives us a new way to think about how diabetes can affect kidneys and other organs." 

Benjamin Freedman, Associate Professor, University of Washington

Importantly, drug treatments that reduced the over-activation of distinct inflammatory pathways protected the kidney organoids from damage even when they remained exposed to high sugar levels. The findings suggest that inflammation may be a primary trigger of kidney damage in DKD and that targeting dysregulated inflammatory pathways could offer a potential strategy for preventing or treating the disease. Careful preclinical and clinical evaluation will be needed to identify and test specific inhibitors before such approaches could potentially be used in patients.

DKD is a major complication of diabetes, affecting about 40% of people with the disease. Persistently high blood sugar can damage the kidneys over time, potentially leading to kidney failure and the need for dialysis or transplantation. Current management includes lifestyle changes and medications to control blood sugar and blood pressure, but few treatments directly target kidney damage.

To better understand how that damage develops and explore new treatment approaches, the researchers created a laboratory model of DKD using kidney organoids. These organoids are generated from stem cells through a stepwise process that recapitulates aspects of kidney development. Once formed, they resemble features of human kidneys in their cellular composition and function, providing an accessible model for studying human kidney biology and disease. The researchers modeled diabetic conditions by exposing the organoids to high sugar levels similar to those occurring in patients with diabetes, enabling them to investigate both the resulting kidney damage and potential ways to prevent it.