Upregulated C1qa Signaling Antagonizes Glomerular Health in Aged Kidneys

Background: Renal aging is closely associated with the prevalence of end-stage renal disease requiring renal replacement therapy and a higher incidence with lower recovery rates of acute kidney injury. The progressive structural changes and decline in glomerular number during renal aging contribute to a decrease in estimated glomerular filtration rate, an increase in albuminuria, and the development of age-related kidney diseases. Despite its clinical significance, the underlying mechanisms driving glomerular aging remain inadequately understood. Methods: To investigate the specific changes occurring in glomeruli over time, we performed RNA-sequencing on glomeruli isolated from young (2 months old), intermediate (12 months old), and old (24 months old) mice. This approach allowed us to focus on the glomerular enrichment and identify age-related alterations. Our findings revealed significant alterations in genes associated with immune system processes, innate immune responses, inflammatory responses, and chemotaxis between 12- and 24-months old glomeruli. Results: Among the upregulated complement pathways, the classical complement pathway stood out as the most prominent during glomerular aging. Specifically, the genes encoding complement 1 (C1) elements, including C1r, C1s, C1qa, C1qb, and C1qc, showed increased expression. These upregulated complement gene signatures were particularly observed in aged podocytes. Immunostaining of C1qa in human kidneys also demonstrated an age-dependent increase. To further investigate the role of C1qa in podocytes, we transduced C1qa lentivirus into podocytes and observed that the upregulated C1qa signaling significantly increased reactive oxygen species production and aggravated albumin permeability. Conclusion: In summary, our transcriptome analysis has advanced our understanding of the molecular mechanisms involved in glomerular aging. Furthermore, it provides evidence for the crucial role of increased C1qa signaling in glomerular aging. These findings shed light on potential therapeutic targets and strategies to mitigate age-related kidney diseases.