Integrated proteomic-transcriptomic profiling identifies NR3C2 up-regulation and a candidate plasma-protein-handling signature in chronic podocyte injury.

Abstract

The advanced stages of chronic kidney disease (CKD) are difficult to reverse, yet their protein-level pathology remains poorly defined. We analysed the kidney proteome of Pod-TRECK mice, a model of podocyte-driven CKD, at Day 14 and Day 21, representing the progression and late phases, respectively. We then integrated these proteomic data with group-average fold changes from a corresponding time-point transcriptomic dataset generated from separate cohorts of mice using the same model. Although renal function is known to worsen from Day 14 to Day 21 in this model, the bulk-kidney proteome changed only modestly over this interval. Concordance between protein and transcript fold changes also decreased, indicating that late disease progression involves protein-level changes that are not fully reflected by steady-state mRNA abundance. This late-phase signature was distributed across multiple protein groups. NR3C2, the mineralocorticoid receptor, was upregulated at the protein level without a corresponding change in transcript abundance, as further validated by immunohistochemistry. Being the pharmacological target of finerenone, NR3C2 represents a clinically relevant protein-level change that transcriptomic profiling alone would miss. A subset of plasma-derived proteins also accumulated in injured mouse kidneys without matching local transcript induction. A similar pattern was observed in human CKD kidney tissue, while related plasma proteins were reduced in patients with rapid CKD progression. Complement C5 was one prominent member of this candidate plasma-protein-handling signature. Together, these findings show that the late phase of podocyte-driven CKD involves distributed protein-level remodelling, including an RNA-discordant increase in NR3C2 protein and a candidate plasma-protein-handling signature.