Stress in the kidney is the road to pERdition: is endoplasmic reticulum stress a pathogenic mediator of diabetic nephropathy?

Abstract

The endoplasmic reticulum (ER) is an organelle that primarily functions to synthesise new proteins and degrade old proteins. Owing to the continual and variable nature of protein turnover, protein synthesis is inherently an error-prone process and is therefore tightly regulated. Fortunately, if this balance between synthesis and degradation is perturbed, an intrinsic response, the unfolded protein response (UPR) is activated to restore ER homoeostasis through the action of inositol-requiring protein 1, activating transcription factor 6 and PKR-like ER kinase transmembrane sensors. However, if the UPR is oversaturated and misfolded proteins accumulate, the ER can shift into a cytotoxic response, a physiological phenomenon known as ER stress. The mechanistic pathways of the UPR have been extensively explored; however, the role of this process in such a synthetic organ as the kidney requires further clarification. This review will focus on these aspects and will discuss the role of ER stress in specific resident kidney cells and how this may be integral in the pathogenesis and progression of diabetic nephropathy (DN). Given that diabetes is a perturbed state of protein turnover in most tissues, it is important to understand if ER stress is a secondary or tertiary response to other changes within the diabetic milieu or if it is an independent accelerator of kidney disease. Modulators of ER stress could provide a valuable tool for the treatment of DN and are under active investigation in other contexts. Key Words" endoplasmic reticulum stress " diabetic nephropathy

Soluble epoxide hydrolase in podocytes is a significant contributor to renal function under hyperglycemia

“…Endoplasmic reticulum (ER) stress is implicated in the pathogenesis of DN [21], and sEH deficiency and pharmacological inhibition attenuate ER stress [22, 23]. Accordingly, the effects of podocyte sEH deficiency on renal ER stress were determined in control and pod-sEHKO mice under normoglycemia and STZ- and HFD-induced hyperglycemia.…”

“…In line with decreased ER stress, podocyte sEH deficiency attenuated hyperglycemia-induced NF-κB inflammatory response. ER stress is implicated in the pathogenesis of DN [21], and chemical chaperones that mitigate ER stress slow DN progression [46, 47]. Hence, it is reasonable to stipulate that the renal protective effects of podocyte sEH deficiency under hyperglycemia are mediated, at least partly, by decreased ER stress.…”

Diabetes and Age-Related Differences in Vascular Function of Renal Artery: Possible Involvement of Endoplasmic Reticulum Stress

“…13,16,17 Recently, several studies have demonstrated that dysfunction of the ER, or ER stress, is involved in the pathogenesis of diabetes and its complications and the aging process. 14,16,[18][19][20][21][22] Moreover, some reports have suggested the association between ER stress and the vascular function in pathophysiological states. Spitler et al 23 reported that ER stress was increased in the spontaneously hypertensive rat (SHR) aorta, and treatment with chemical chaperones, such as tauroursodeoxycholic acid (TUDCA) and 4-phenylbutyric acid (PBA), ameliorated the increased EDCF-mediated contraction via suppression of the cytosolic phospholipase A 2 (cPLA 2 )/COX pathway.…”

Structure–activity relationship of piperine and its synthetic amide analogs for therapeutic potential to prevent experimentally induced ER stress in vitro

“…It plays a principal role in controlling the synthesis, folding and maturation of luminal, secreted and transmembrane proteins (Brandizzi et al 2014;Staehelin 1997;Zhuang and Forbes 2014). During protein synthesis, only those proteins folded in proper configuration and underwent specific post-translational modifications will be processed through the ER secretory pathway and translocated to Golgi bodies (Zhuang and Forbes 2014).…”