Spatiotemporal landscape of kidney tubular responses to glomerular proteinuria

Abstract Abstract Background Large increases in glomerular protein filtration induce major changes in body homeostasis and increase risk of renal 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 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 Glomerular proteinuria activates large-scale and pleotropic 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 triggers dramatic expansion of a hybrid S1/2 population, followed by injury and failed repair, with the cumulative effect of sustained loss of canonical S2 functions. Proteinuria also induces acute injury in S3. 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 causes distinct patterns of remodeling and injury 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 tubular cell plasticity.