Diabetic kidney disease is one of the most common and serious complications of diabetes, yet the chain of events linking high blood sugar to kidney damage remains incompletely understood. Now, a stem cell-based model suggests that glucose itself may help trigger an inflammatory response inside kidney tissue—one that can damage key epithelial cells.
Researchers led by Benjamin S. Freedman, PhD, at the University of Washington and University of Miami, report that human kidney organoids exposed to elevated glucose developed tissue-intrinsic inflammation and epithelial cell detachment, including detachment of podocytes, specialized cells essential for the kidney’s filtration barrier. The study, “Elevated glucose in kidney organoids induces tissue-intrinsic inflammation driving epithelial detachment,” was published recently in Stem Cell Reports.
“High sugar causes inflammation in these organoids even though they lack an immune system,” Freedman said. “This was unexpected and gives us a new way to think about how diabetes can affect kidneys and other organs.”
Diabetic kidney disease affects about 40% of people with diabetes and can progress to kidney failure due to persistently high blood pressure. Although current therapies can help control blood sugar and blood pressure, few treatments directly address the cellular damage that occurs in the kidney. The researchers set out to model that damage using human kidney organoids, which are generated from pluripotent stem cells through a stepwise differentiation process that recapitulates aspects of kidney development.
To mimic diabetic conditions, the team cultured kidney organoids in media containing different glucose concentrations. Organoids maintained in lower glucose conditions remained largely intact, but those exposed to higher glucose levels showed progressive morphological deterioration. Importantly, live/dead and lactate dehydrogenase assays suggested the changes were not caused by overt cytotoxicity. Instead, the researchers observed detachment of podocytes and tubular epithelial cells from the main organoid body, a phenotype reminiscent of changes reported in kidney biopsies and urine samples from patients with diabetic kidney disease.
Single-cell RNA sequencing pointed to activation of inflammatory pathways in the high-glucose organoids. MIF emerged as the top upregulated gene across the complete dataset, epithelial cluster, and podocyte subcluster, while TNF-alpha/NF-kB signaling was among the pathways enriched in epithelial and proximal tubule subclusters. Several pathway-level changes, including TNF-alpha/NF-kB signaling, also overlapped with transcriptomic data from human diabetic kidney disease biopsies. “Thus, our scRNA-seq analysis suggested that high glucose levels promote TNF-alpha and MIF expression, driving inflammation and podocyte injury,” the authors wrote.
The researchers then tested whether blocking these inflammatory pathways could blunt the injury phenotype. Inhibiting MIF with ISO-1 or TNF-alpha with etanercept protected organoids from podocyte injury under high-glucose conditions. MAPK pathway inhibitors also partially rescued podocyte morphology. These findings suggest that inflammation may be more than a secondary consequence of diabetic kidney damage.
The authors caution that further work is needed before these findings can be translated into patient therapies. The model required relatively high glucose levels to induce injury in the absence of TNF-alpha, and organoids lack a functional vasculature and immune system. Still, the study provides a controlled human platform for dissecting how hyperglycemia affects kidney cells and for evaluating potential anti-inflammatory strategies.
“While our findings suggest that inhibitors of MIF, TNF-alpha, or MEK can be used to intervene in this process, careful consideration and preclinical studies are needed to determine which of these treatment strategies is likely to be most effective,” the authors wrote.
