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

Abstract

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 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 (mCCDcl1) cells. Exposure of mCCDcl1 cells to albumin induced NF-κB activation as assessed by luciferase reporter gene assay, nuclear translocation of NF-κB p65 subunit, and increased NF-κB target gene expression. Moreover, albuminuria-like condition results in transforming growth factor-β1 (TGF-β1) overexpression and the upregulation of profibrotic signaling markers such as Snail or vimentin via an autocrine mechanism. In mCCDcl1 cells, neutrophil gelatinase-associated lipocalin (NGAL)/lipocalin-2/24p3 receptor (24p3R) mediates albumin endocytosis as well as activation of NF-κB and TGF-β1 signaling pathways. Therefore, CD may play a key role in initiation and/or progression of inflammation and fibrosis in response to proteinuria.

Proteinuria Increases Plasma Phosphate by Altering Its Tubular Handling

“…Because albumin is also reabsorbed both in the proximal and distal nephron, 8 we reasoned that it may also alter Klotho expression. As revealed by Western blot of the kidney cortex, Klotho expression was decreased in proteinuric rats ( Figure 4, A and B).…”

“…Recently, we demonstrated that albumin uptake also occurs in distal segments of the renal tubule, in part via 24p3R, a neutrophil gelatinase-associated lipocalin receptor expressed in the distal convoluted tubule and cortical and medullary collecting duct. 8 Proteinuria has been associated with renal dysfunction via a direct toxic effect on proximal tubular cells and the distal nephron. 8,9 High plasma phosphate, even in the upper normal range, is correlated with increased cardiovascular risk, independent of renal function.…”

“…8 Proteinuria has been associated with renal dysfunction via a direct toxic effect on proximal tubular cells and the distal nephron. 8,9 High plasma phosphate, even in the upper normal range, is correlated with increased cardiovascular risk, independent of renal function. [10][11][12] This correlation might be explained by a direct phosphate vascular toxicity.…”

Prevention of apoptosis averts glomerular tubular disconnection and podocyte loss in proteinuric kidney disease

“…It is well documented that excessive uptake of albumin into RPTC triggers apoptosis 30,41–43 and generation of pro-fibrotic factors, such as TGF-beta 44 . To determine the order by which these processes are initiated, we incubated RPTC with fatty acid and endotoxin-free albumin (10 mg/mL) for 2, 4, 8 and 18 hours.…”

Proteinuria: it is time to look beyond the proximal tubule

“…In a recent issue of American Journal of Physiology-Renal Physiology, Dizin et al (2) have presented convincing evidence that proximal tubule may not be the only culprit in proteinuria induced tubulointerstitial injury. Their data suggested that proteinuria-induced damage may be multifaceted and a more thorough examination of distal nephron may be required to elucidate the cause of proteinuria induced tubulointerstitial damage in proteinuric states.…”