Diversion of Arginine’s dietary metabolic fate in proteinuric kidney disease

Abstract Proteinuria predicts chronic kidney disease progression and cardiometabolic mortality, yet how sustained urinary protein loss reshapes interorgan metabolism remains unclear. Here, we tested whether proteinuric kidney disease alters whole-body amino-acid and nitrogen handling by applying long-term dietary arginine isotope tracing in a proteinuric podocin-mutant mouse model, complemented by ex vivo nephron-segment metabolism and human cohort analyses. Because arginine connects amino acid use in protein synthesis, amino acid catabolism, and the urea cycle, the dietary isotope label allowed us to follow both metabolite flux and protein incorporation across organs over time. Proteinuria did not trigger a broad compensatory increase in protein synthesis. Instead, it caused a kidney-centered rerouting of arginine metabolism. Arginine use shifted away from hepatic ureagenesis and toward renal glutamate-, proline-, and aspartate-linked fate. Across organs, most proteins incorporated recycled arginine, whereas albumin preferentially incorporated diet-derived arginine, identifying albumin as a major non-recycled arginine sink during proteinuric disease. In the kidney, proximal nephron segments showed coordinated remodeling of arginine and proline metabolism in association with tubular albumin handling. This rerouting favored proline synthesis and early collagen incorporation before overt fibrosis was established. Isotope-resolved nitrogen tracing indicated that this renal diversion of arginine occurs at the expense of coordinated nitrogen and acid handling, as reflected by reduced urinary ammonium excretion, tissue accumulation of arginine-derived ammonia, and altered abundance of enzymes involved in ammonium detoxification. In humans, circulating aspartate was elevated during active proteinuric disease and decreased in remission, independently of glomerular filtration rate, and both aspartate and proline associated with histological markers of fibrotic remodeling in biopsies from glomerular disease patients. Consequently, in proteinuric mice, a high dietary content of aspartate/asparagine further aggravated collagen accumulation and fibrosis-related remodeling of high-proline-content proteins, while impairing acid excretion. Together, these findings define proteinuric kidney disease as a chronic interorgan nitrogen-redistribution state that links selective protein turnover, impaired ammonium disposal, acid retention, and a renal profibrotic metabolic environment.