Spatiotemporal Landscape of Kidney Tubular Responses to Glomerular Proteinuria

Abstract

Key Points Glomerular proteinuria induces large-scale changes in gene expression along the nephron.Increased protein uptake in the proximal tubule results in axial remodeling and injury.Increased protein delivery to the distal tubule causes dedifferentiation of the epithelium. Background Large increases in glomerular protein filtration induce major changes in body homeostasis and are associated with a higher risk of kidney functional decline and cardiovascular disease. We investigated how elevated protein exposure modifies the landscape of tubular function along the entire nephron, to understand the cellular changes that mediate these important clinical phenomena. Methods We conducted single-nucleus RNA sequencing, functional intravital imaging, and antibody staining to spatially map transport processes along the mouse kidney tubule. We then delineated how these were altered in a transgenic mouse model of inducible glomerular proteinuria (POD-ATTAC) at 7 and 28 days. Results Glomerular proteinuria activated large-scale and pleiotropic changes in gene expression in all major nephron sections. Extension of protein uptake from early (S1) to later (S2) parts of the proximal tubule initially triggered dramatic expansion of a hybrid S1/2 population, followed by injury and failed repair, with the cumulative effect of loss of canonical S2 functions. Proteinuria also induced acute injury in S3. Meanwhile, overflow of luminal proteins to the distal tubule caused transcriptional convergence between specialized regions and generalized dedifferentiation. Conclusions Proteinuria modulated cell signaling in tubular epithelia and caused distinct patterns of remodeling and injury in a segment-specific manner.