Spatiotemporal landscape of kidney tubular responses to glomerular proteinuria

Abstract Background Large increases in glomerular protein filtration induce major changes in kidney function and body homeostasis, and increase the risk of cardiovascular disease. We investigated how elevated protein exposure modifies the landscape of tubular function along the entire nephron, to better understand the cellular changes that mediate these important clinical phenomena. Methods We conducted single nuclei RNA sequencing, functional intravital imaging, and antibody staining to spatially map transport processes along the mouse kidney tubule. We then delineated how these are altered in a transgenic mouse model of inducible glomerular proteinuria (POD-ATTAC) at 7 and 28 days. Results were compared to an ischemia-reperfusion injury (IRI) model of tubular damage. Results Glomerular proteinuria activates large-scale and pleotropic changes in tubular cell gene expression in all major nephron sections, and an injury profile that partially overlaps with IRI, suggesting the existence of both specific and non-specific responses. Extension of protein uptake from the early to late part of the proximal tubule results in a substantial shift in the balance of reabsorptive and secretory pathways. Meanwhile, overflow of luminal proteins to the distal tubule causes transcriptional convergence between specialized regions and generalized dedifferentiation. Conclusion Proteinuria is a potent modulator of cell signaling in tubular epithelia and triggers extensive remodeling, in a segment specific manner. These findings could explain some of the well-recognized clinical complications that arise in proteinuric kidney disease, and may also be important for understanding nephron patterning in organ development.