The kidney is essential for maintaining whole-body homeostasis through tightly regulated processes of glomerular filtration, followed by tubular reabsorption and secretion to generate excreted urine. Within the nephron, the proximal tubule (PT) reabsorbs most of the filtered sodium, water, and nutrients, using both adenosine triphosphate (ATP)-dependent transcellular mechanisms and passive energy-free paracellular transport mediated by claudin proteins, notably claudin-2. In pathological states such chronic kidney disease (CKD), nephron loss induces compensatory hyperfiltration and increased PT workload, which may drive tubular injury, hypoxia, and fibrosis.

We hypothesize that loss of claudin-2–mediated Na+ permeability shifts transport toward ATP-consuming transcellular pathways, thereby increasing oxygen demand and accelerating CKD progression. To test this, we used a murine model of podocyte depletion that generates heavy proteinuria which generates first acute and then chronic tubular injury. Using this model, we will assess the effects of claudin-2 deficiency on Na+ handling, tubular functions, and disease progression. Our findings identify claudin-2 as a key regulator of renal energy homeostasis and highlight its potential as a therapeutic target to mitigate PT injury and slow CKD progression.