Phosphoenolpyruvate carboxykinase 1 (PCK1) is highly expressed in the proximal tubule. We show here that this enzyme is crucial for the maintenance of normal tubular physiology, lactate, and glucose homeostasis. PCK1 is a regulator of acid-base balance and ammoniagenesis. Preventing PCK1 downregulation during renal injury improves renal function, rendering it an important target during renal disease.

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. Podcast: This article contains a podcast at https://dts.podtrac.com/redirect.mp3/www.asn-online.org/media/podcast/JASN/2024_05_01_ASN0000000000000357.mp3

Chronic kidney disease (CKD) is a major global health problem, with substantial associated morbidity and mortality. Fibrosis is the final common pathway of organ damage in CKD, so understanding how this arises during kidney injury is critical for building a holistic picture of the pathogenesis. Here, using gene expression data, intravital microscopy in mice and realistic cell models, we uncover evidence of a signaling pathway linking tubular pyrimidine metabolism and injury-evoked extracellular uridine diphosphate (UDP) release to activation of the P2Y6 receptor (P2Y6R) in surrounding fibroblasts. We show that P2Y6R activation triggers intracellular calcium rises, which stimulate fibroblast proliferation, migration, and conversion towards a myofibroblast phenotype. Conversely, genetic knockout or pharmacological blockade of the P2Y6R reduces fibrosis in mice with CKD. Thus, we reveal that pyrimidinergic calcium signaling couples fibroblast responses to changes in tubular metabolism in disease states, and represents a potential new target for therapeutic intervention.

Dent disease type 1 is a rare X-linked recessive inherited renal disorder affecting mainly young males, generally leading to end-stage renal failure and for which there is no cure. It is caused by inactivating mutations in the gene encoding ClC-5, a 2Cl⁻/H⁺ exchanger found on endosomes in the renal proximal tubule. This transporter participates in reabsorbing all filtered plasma proteins, which justifies why proteinuria is commonly observed when ClC-5 is defective. In the context of Dent disease type 1, a proximal tubule dedifferentiation was shown to be accompanied by a dysfunctional cell metabolism. However, the exact mechanisms linking such alterations to chronic kidney disease are still unclear. In this review, we gather knowledge from several Dent disease type 1 models to summarize the current hypotheses generated to understand the progression of this disorder. We also highlight some urinary biomarkers for Dent disease type 1 suggested in different studies.

The kidney proximal tubule is a highly specialized epithelium that transports metabolites and maintains body homeostasis. Cells lining this nephron segment are densely packed with lysosomes, but little is known about the dynamic activity of these organelles in situ. Here, using targeted sensors and live cell and intravital imaging we track acidified lysosomes along the mouse proximal tubule and uncover marked axial heterogeneity in their distribution, characteristics and organellar interactions. In the early part, cathepsin-rich lysosomes frequently contact with apical endosomes to receive and catabolize filtered plasma proteins. Conversely, in the later region, lipase-containing lysosomes traverse cells to mobilize and degrade mitochondria-associated lipid droplets and facilitate their extrusion into the tubular lumen. Acutely de-acidifying lysosomes dramatically alters their movement, causing major changes in tubular protein and lipid processing. Thus, lysosomes in proximal tubules are highly dynamic and adapted to perform distinct metabolic tasks within different specialized segments.