Albuminuria induces a proinflammatory and profibrotic response in cortical collecting ducts via the 24p3 receptor

作者：Dizin Eva; Hasler Udo; Nlandu Khodo Stellor; Fila Marc; Roth Isabelle; Ernandez Thomas; Doucet Alain; Martin Pierre Yves; Feraille Eric; de Seigneux Sophie^*

来源：American Journal of Physiology - Renal Fluid and Electrolyte Physiology, 2013, 305(7): F1053-F1063.

DOI：10.1152/ajprenal.00006.2013

• proteinuria
• collecting duct
• 24p3R
• fibrosis

Albuminuria is strongly associated with progressive kidney tubulointerstitial 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 proinflammatory and profibrotic response, we assessed the effect of albuminuria in the collecting duct (CD). With the use of kidney sections and isolated cortical CDs (CCDs) 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 profibrotic 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 (mCCD(cl1)) cells. Exposure of mCCD(cl1) cells to albumin induced NF-kappa B activation as assessed by luciferase reporter gene assay, nuclear translocation of NF-kappa B p65 subunit, and increased NF-kappa B target gene expression. Moreover, albuminuria-like condition results in transforming growth factor-beta(1) (TGF-beta(1)) overexpression and the upregulation of profibrotic signaling markers such as Snail or vimentin via an autocrine mechanism. In mCCD(cl1) cells, neutrophil gelatinase-associated lipocalin (NGAL)/lipocalin-2/24p3 receptor (24p3R) mediates albumin endocytosis as well as activation of NF-kappa B and TGF-beta(1) signaling pathways. Therefore, CD may play a key role in initiation and/or progression of inflammation and fibrosis in response to proteinuria.

• 出版日期2013-10