A new study using a 1-million-cell atlas shows heterogeneity in kidney cell responses to diabetic kidney disease and treatments. Published in Cell Metabolism, the research used the largest mouse kidney single-cell atlas to date. The results suggest that combination therapy should be used to treat patients who are un-responsive to current treatments.
The work was conducted by a team of US researchers from the Division of Nephrology at Washington University’s Department of Medicine, the CVM Janssen Research and Development in Boston and the Tox LJ Janssen Research and Development in California. The researchers analysed the response of a mouse model to five treatment regimens using single-cell RNA sequencing (scRNA-seq).
Diabetic kidney disease
Diabetes is estimated to affect over 422 million people worldwide and 1.5 million deaths are directly attributed to diabetes each year. According to the World Health Organisation, both the number of cases and the prevalence of diabetes have been steadily increasing over the past few decades.
Diabetic kidney disease (DKD) arises in around 40% of patients with diabetes and causes kidney failure, cardiovascular disease and premature death and new therapeutic options are sought after.
While sodium-glucose cotransporter-2 inhibitors (SGLT2i) have emerged as a promising drug class for the treatment of DKD, their mechanism of action remains unknown.
The authors stated, “Deciphering the cellular and molecular drivers of DKD, and how best to target the main drivers of poor outcomes therapeutically, is a top priority.”
The pathogenesis of DKD is multifactorial, including inflammation, glomerulosclerosis, systemic hypertension and kidney microvascular damage.
ScRNA-seq allows the construction of detailed cell atlases depicting cell type and state in health and disease. Given the multitude of cell types affected in DKD, using scRNA-seq could provide further insight into the drivers of DKD and cell-specific responses to different drug treatments, including SGLT2 inhibition.
The researchers generated scRNA-seq datasets from groups comprising of nearly 1 million cells. The study utilised the homozygous Lepr knockout (db/db) mouse model with uninephrectomy and renin-induced hypertension mouse model.
“To our knowledge, this is the largest mouse kidney single-cell atlas to date,” the authors reported.
Analysis of the resulting atlas revealed that different medications affected strikingly different cell types.
The authors discovered that combination therapy had the largest effects. In addition, these effects were also largely non-overlapping. The researchers found that combination therapy of ACEi + rosiglitazone or ACEi + SGLT2i had the strongest normalising effect, and this was not simply additive of either monotherapy alone.
Shedding light on the promising drug class, the results suggested that SGLT2i induces fasting mimicry and hypoxia responses. The authors proposed that SGLT2i accomplish their protective effects by regulating alternative splicing.
These non-overlapping transcriptional effects may reflect residual disease mechanisms not targeted by current therapies. These might be exploited through future combination therapies to treat patients unresponsive to current standards of care, since different drug classes target different cell types in kidney.
To add further value, the authors generated a data visualization tool that can be accessed online.
The authors said, “The differentially expressed genes identified in this atlas of DKD and its treatment can be used to gain mechanistic insight as well as serving as potential biomarkers for diagnostics.”
Written by Poppy Jayne Morgan, Front Line Genomics
Image Credit: Canva