Crosstalk between the Unfolded Protein Response and NF-κB-Mediated Inflammation in the Progression of Chronic Kidney Disease

Abstract

The chronic inflammatory response is emerging as an important therapeutic target in progressive chronic kidney disease. A key transcription factor in the induction of chronic inflammation is NF-κB. Recent studies have demonstrated that sustained activation of the unfolded protein response (UPR) can initiate this NF-κB signaling phenomenon and thereby induce chronic kidney disease progression. A key factor influencing chronic kidney disease progression is proteinuria and this condition has now been demonstrated to induce sustained UPR activation. This review details the crosstalk between the UPR and NF-κB pathways as pertinent to chronic kidney disease. We present potential tools to study this phenomenon as well as potential therapeutics that are emerging to regulate the UPR. These therapeutics may prevent inflammation specifically induced in the kidney due to proteinuria-induced sustained UPR activation.

Is Progressive Chronic Kidney Disease a Slow Acute Kidney Injury?

“…10,13,15,16,17,18 One of these maladaptive cellular responses is associated with accumulation of inappropriately processed or unfolded proteins in the endoplasmic reticulum (ER). 17,22 Cellular adaptations to ER dysregulation are initiated to adjust the translation, translocation, folding, and degradation of ER proteins as protective mechanisms, but they simultaneously promote cellular autophagy. 17,22 Autophagy is a cellular "cleanup" process in which damaged cytosolic constituents and organelles are encapsulated in autophagosomes and degraded for reutilization in cytosolic lysosomes.…”

“…However, in experimental models of kidney diseases, the misfolded protein-induced dysfunction of the ER and mitochondria can stimulate pro-inflammatory responses via nuclear factor-κB (NF-κB) upregulation and mediation of transcription of target genes for inflammatory interleukins, tumor necrosis factor-α, and adhesion molecules. 17,22 Sustained or severe cellular stresses over stimulate these adaptive responses and activate downstream signaling pathways for apoptosis of the disrupted cell.…”

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.…”

“…[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.…”

HMGB1, TGF‑β and NF‑κB are associated with chronic allograft nephropathy

“…NF-κB is a protein complex, which has an important role in transcription, immune responses and inflammation developments (23,24). The NF-κB family is a family of inducible transcription factors that have been demonstrated to contribute to the process of renal inflammation and immunological disease development (25,26). Transforming growth factor β (TGF-β) is a multi-function cytokine complex with three isoforms, TGF-β1, TGF-β2, and TGF-β3 (27).…”