Multimodal single cell sequencing implicates chromatin accessibility and genetic background in diabetic kidney disease progression

Abstract

The proximal tubule is a key regulator of kidney function and glucose metabolism. Diabetic kidney disease leads to proximal tubule injury and changes in chromatin accessibility that modify the activity of transcription factors involved in glucose metabolism and inflammation. Here we use single nucleus RNA and ATAC sequencing to show that diabetic kidney disease leads to reduced accessibility of glucocorticoid receptor binding sites and an injury-associated expression signature in the proximal tubule. We hypothesize that chromatin accessibility is regulated by genetic background and closely-intertwined with metabolic memory, which pre-programs the proximal tubule to respond differently to external stimuli. Glucocorticoid excess has long been known to increase risk for type 2 diabetes, which raises the possibility that glucocorticoid receptor inhibition may mitigate the adverse metabolic effects of diabetic kidney disease.

Predicting regulators of epithelial cell state through regularized regression analysis of single cell multiomic sequencing

“…FR-PTC cells have been identified in healthy human kidney samples derived from tumor-adjacent tissue after partial nephrectomy(14,28). We hypothesize that FR-PTC in apparently healthy kidneys is attributable to subacute injury or stress sustained over a patient’s lifetime, leading to accumulation of FR-PTC cells and a fibrosis-promoting phenotype.…”

“…Mouse FR-PT cells closely resemble a human proximal tubule state, PT_VCAM1, that is marked by VCAM1 expression and has been identified in healthy, non-AKI, human kidney(14,27). The PT_VCAM1 population increases with age and in diabetic kidney disease (10,14,28).…”

“…Mouse FR-PT cells closely resemble a human proximal tubule state, PT_VCAM1, that is marked by VCAM1 expression and has been identified in healthy, non-AKI, human kidney(14,27). The PT_VCAM1 population increases with age and in diabetic kidney disease (10,14,28). Although FR-PT arise after acute injury, the transcriptionally similar PT_VCAM1 state is present even in healthy kidneys and we hypothesize it represents a “wear and tear” or injury in situ state, even in the absence of clinical AKI.…”

“…Profibrotic, proinflammatory PT cell states have been increasingly predicted to play a role in CKD development following incomplete PT repair following acute injury or during chronic progressive disease (10,14,28,56). Here we performed joint single nucleus RNA and ATAC sequencing on adult human kidney samples to study the PT_VCAM1 state in adult human kidney.…”

“…population increases with age and in diabetic kidney disease (10,14,28). Although FR-PT arise after acute injury, the transcriptionally similar PT_VCAM1 state is present even in healthy kidneys and we hypothesize it represents a "wear and tear" or injury in situ state, even in the absence of clinical AKI.…”