Spatiotemporal Landscape of Kidney Tubular Responses to Glomerular Proteinuria

Abstract

Background Large increases in glomerular protein filtration induce major changes in body homeostasis and increase 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 nuclei 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 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 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 causes distinct patterns of remodeling and injury in a segment specific manner.

From the Beginning to the End: Effects of Proteinuria along the Renal Tubule

“…In this issue of JASN, Faivre et al apply an elegant combination of intravital imaging and single-nuclei RNA-sequencing to shed new light on tubular protein handling and the effects of glomerular proteinuria on transcriptional state and function of different cell types along the consecutive segments of nephrons in mice. 5 The authors present three key findings: (1) The kidney adapts to proteinuria by extending the protein reabsorption capacity from segment 1 to segment 2 of the proximal tubule. (2) Proteinuria causes tubular remodeling and injury.…”

“…8 This finding could furthermore relate to the reduced effect of loop diuretics in end stage kidney disease, since loop diuretics have to be secreted through organic anion transport processes to exert their function. 5 Using single-nuclei RNA-sequencing, the authors show that proteinuria results in appearance of dedifferentiated, injured proximal tubule cells. They describe a failed-repair proximal tubule cell population, which has striking similarities to injured proximal tubule cells observed in mouse models of ischemic AKI, although the spatiotemporal dynamics of proximal tubule injury differ between the diseases.…”

“…They describe a failed-repair proximal tubule cell population, which has striking similarities to injured proximal tubule cells observed in mouse models of ischemic AKI, although the spatiotemporal dynamics of proximal tubule injury differ between the diseases. 5,9 These failed-repair proximal tubule cells express the injury marker Vcam1 (encoding vascular cell adhesion molecule 1). Vcam1 has also been shown to be upregulated in proximal tubule cells in other kidney diseases, such as diabetic kidney disease and autosomal dominant polycystic kidney disease.…”