Endoplasmic reticulum stress drives proteinuria-induced kidney lesions via Lipocalin 2

Abstract

In chronic kidney disease (CKD), proteinuria results in severe tubulointerstitial lesions, which ultimately lead to end-stage renal disease. Here we identify 4-phenylbutyric acid (PBA), a chemical chaperone already used in humans, as a novel therapeutic strategy capable to counteract the toxic effect of proteinuria. Mechanistically, we show that albumin induces tubular unfolded protein response via cytosolic calcium rise, which leads to tubular apoptosis by Lipocalin 2 (LCN2) modulation through ATF4. Consistent with the key role of LCN2 in CKD progression, Lcn2 gene inactivation decreases ER stress-induced apoptosis, tubulointerstitial lesions and mortality in proteinuric mice. More importantly, the inhibition of this pathway by PBA protects kidneys from morphological and functional degradation in proteinuric mice. These results are relevant to human CKD, as LCN2 is increased in proteinuric patients. In conclusion, our study identifies a therapeutic strategy susceptible to improve the benefit of RAS inhibitors in proteinuria-induced CKD progression.

The Lipocalin LPR-1 Cooperates with LIN-3/EGF Signaling To Maintain Narrow Tube Integrity in Caenorhabditis elegans

“…Tear lipocalin transports and/or sequesters phospholipids within the tear film to enable proper lubrication of the eye (Glasgow et al 1995;Gouveia and Tiffany 2005). Lipocalin2 (Lcn2, also known as 24p3 or neutrophil gelatinase associated lipocalin) sequesters iron-containing siderophores to protect against bacterial infections (Flo et al 2004), and can influence signaling by hepatocyte growth factor during kidney tube development (Wu and Han 1994;Gwira et al 2005;El Karoui et al 2016). The lipocalin Swim (secreted interacting Wnt molecule) facilitates transport of lipid-modified Wnt ligands (Mulligan et al 2012), and the plasma lipocalin apolipoprotein M (ApoM) facilitates transport of the signaling lipid sphingosine-1-phosphate (S1P) (Christoffersen et al 2011).…”

The Unfolded Protein Response: A Novel Insight into Chronic Kidney Disease (CKD)

“…9 In this case, the PERK arm of the UPR may also trigger activation of ATF4, a transcription factor that increases the transcription of pro-apoptoticgenes such as CHOP (CCAAT-enhancer-binding protein homologous protein) and decreases antiapoptotic genes such as B-cell lymphoma 2 (Bcl-2). [1][2][3]8 Furthermore, the IRE1α arm may also activate Caspase 12 (rodents)/Caspase 4 (humans) and c-Jun N-terminalkinase (JNK) phosphorylation, leading to initiation of pro-apoptotic pathways. 3 Thus, the UPR is a double-edged sword acting as either a cell-protective machinery during mild ER stress or a cell-destructive terminator during severe or long-term ER stress.…”

“…Interestingly, accumulating evidence has shown the association of ER stress and dysregulated UPR with the pathogenesis of CDK. [1][2][3][4][5][6][7][8] Several lines of evidence from clinical and experimental studies have revealed that the accumulation of misfolded proteins of the slit diaphragm elicits ER stress-associated renal injury and proteinuria. 1,2 It has been demonstrated that various pathogenic factors, such as proteinuria, hyperglycemia, and uremic toxins, induce UPR-mediated cell apoptosis, compromise the repair capacity of tubular epithelial cells, and accelerate the progression of CKD.…”

“…11 Intriguingly, a high level of LCN2 was found in proteinuric patients with CKD. 8 Animal experiments showed that LCN2 transcription and translation progressively increase in proteinuric mice. 8 Downregulation of LCN2 attenuates ER stress-induced tubular apoptosis, tubulointerstitial lesions and mortality in proteinuric mice.…”

“…8 Animal experiments showed that LCN2 transcription and translation progressively increase in proteinuric mice. 8 Downregulation of LCN2 attenuates ER stress-induced tubular apoptosis, tubulointerstitial lesions and mortality in proteinuric mice. Furthermore, the inhibition of ER stress by 4-phenylbutyric acid protects kidneys from morphological and functional injury in proteinuric mice.…”