Abstract
Pathological insults usually disturb the folding capacity of cellular proteins and lead to the accumulation of misfolded proteins in the endoplasmic reticulum (ER), which leads to so-called “ER stress”. Increasing evidence indicates that ER stress acts as a trigger factor for the development and progression of many kidney diseases. The unfolded protein responses (UPRs), a set of molecular signals that resume proteostasis under ER stress, are thought to restore the adaptive process in chronic kidney disease (CKD) and renal fibrosis. Furthermore, the idea of targeting UPRs for CKD treatment has been well discussed in the past decade. This review summarizes the up-to-date literature regarding studies on the relationship between the UPRs, systemic fibrosis, and renal diseases. We also address the potential therapeutic possibilities of renal diseases based on the modulation of UPRs and ER proteostasis. Finally, we list some of the current UPR modulators and their therapeutic potentials.
Highlights
Kidney diseases have recently received considerable attention because the renal function is vulnerable to pathogenic insults, including inflammation, hypoxia, hypertension, and aging
Renal tubulointerstitial fibrosis is a common pathway of advanced chronic kidney disease (CKD), which is associated with vasoconstriction, capillary obliteration caused by fibrotic expansion, and the formation of a hypoxic microenvironment that worsens renal function [2,3]
Somlo and colleagues reported that site-specific deficiency of XBP1 in podocytes resulted in severe albuminuria, glomerulosclerosis, and kidney fibrosis in a Sec63 and XBP1 double knockout model [89,90]
Summary
Kidney diseases have recently received considerable attention because the renal function is vulnerable to pathogenic insults, including inflammation, hypoxia, hypertension, and aging. ER stress is involved in the progression of organ fibrosis, including those of the kidney, liver, and lung [6]. Because of the limited therapeutic options for the retarding of CKD progression, the modulation of UPRs signaling has become an attractive target for drug discovery [7]. In this mini-review, we discuss the role of UPRs in renal diseases and renal fibrosis, highlight the therapeutic potentials of the modulation of UPRs and the proteostasis of ER, and, in particular, emphasize the role of inositol-requiring protein 1-X-box-binding protein 1 (IRE1-XBP1) signaling
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