Compartment-Specific Immune Remodeling of Renal Aging With C1q-Associated Podocyte Activation

Despite progress in distinguishing glomerular and non-glomerular functions, lifespan transcriptional changes, and how aging differs from CKD adaptation remain unclear. Using RNA sequencing, we performed transcriptional analyses of glomerular compartments, non-glomerular compartments, and whole kidneys from 2-, 12-, and 24-month-old mice. Aging consistently activated immune and inflammatory programs across all parts, yet each displayed distinct immune signatures and immune cell infiltration patterns. Glomerular aging was characterized by a prominent increase in podocyte complement pathway activity, especially C1q expression. In aged podocytes, C1q stimulation was associated with enhanced chemokine expression and phagocytic activity. Tubulointerstitial aging featured marked B cell aggregation and expansion of tertiary lymphoid structures. In renal aging, the major long noncoding RNAs were 5430416N02Rik, Aw112010, and Mir142hg, which were associated with proliferation and immune responses. Comparative analyses with injured fibrotic kidneys revealed differential regulation of adaptive immune cells as a principal discriminator between physiologic aging and chronic kidney disease (CKD) adaptation. These results suggest that aging repatterns the renal immune response in a functional site-specific manner and is distinct from CKD-associated remodeling.