Albuminuria is strongly associated with progressive kidney tubulo-interstitial damage and chronic kidney disease (CKD) progression. In proteinuric nephropathies, albumin reabsorption by the proximal tubule is saturated and the distal nephron is exposed to high concentrations of luminal albumin that may produce adverse effects. Since proximal tubular cells exposed to albuminuria exhibit a pro-inflammatory and pro-fibrotic response, we assessed the effect of albuminuria in the collecting duct (CD). Using kidney sections and isolated cortical CDs (CCD) from puromycin-aminonucleoside-induced nephrotic rats (PAN rats) exhibiting proteinuria, immunofluorescence microscopy revealed internalized albumin in CD cells. In these proteinuric rats, increased expression levels of cytokines and pro-fibrotic signaling markers were detected in isolated CCDs and bands of inflammatory fibrosis could be observed around CDs. Albumin endocytosis was confirmed by FITC-albumin uptake in cultured murine CCD (mCCDcl1) cells. Exposure of mCCDcl1 cells to albumin induced NF-B activation assessed by luciferase reporter gene assay, nuclear translocation of NF-B p65 subunit and increased NF-B target gene expression. Moreover, albuminuria-like conditions results in TGFβ1 over-expression and the up-regulation of pro-fibrotic signaling markers such as Snail or Vimentin via an autocrine mechanism. In mCCDcl1 cells NGAL/lipocalin-2/24p3 receptor (24p3R) mediates albumin endocytosis as well as activation of NF-B and TGFβ1 signaling pathways. Therefore, CD may play a key role in initiation and/or progression of inflammation and fibrosis in response to proteinuria.