Proteinuria and Hyperglycemia Induce Endoplasmic Reticulum Stress

Abstract

The endoplasmic reticulum (ER) is an important site for protein folding and becomes "stressed" when its capacity to fold proteins is overwhelmed. In response, "unfolded protein response" (UPR) genes are induced, increasing the capacity to fold proteins; if the response is insufficient, then apoptosis ensues. For investigation of whether proteinuria and hyperglycemia induce ER stress in renal epithelial cells, microarray data from biopsies of established diabetic nephropathy (DN) were analyzed. Expression of UPR genes was significantly different in these biopsies than in control kidneys or biopsies of patients with mild DN, suggesting an association between the degree of DN and UPR gene expression. Expression of the transcription factor XBP1 and the ER chaperones HSPA5 and HYOU1 were increased, but the proapoptotic gene DDIT3 was unchanged. These findings were replicated in an independent cohort of patients with established DN by real-time reverse transcriptase-PCR. Immunofluorescence of renal biopsies from patients with DN confirmed the upregulation for HSPA5 and HYOU1 proteins in tubular epithelia. In biopsies of minimal-change disease, the mRNA levels of some ER stress molecules were also induced, but protein expression of HSPA5 and HYOU1 remained significantly lower than that observed in DN. Exposure of renal tubular epithelial cells to albumin and high glucose in vitro enhanced expression of genes involved in ER stress. These observations suggest that in proteinuric diseases, tubular epithelial cells undergo ER stress, which induces an adaptive, protective UPR. Although this may protect the cells from ER stress, persistence of hyperglycemia and proteinuria may eventually lead to apoptosis.

Differential expression of endoplasmic reticulum stress-response proteins in different renal tubule subtypes of OVE26 diabetic mice

“…Lack of apoptosis in numerous tubule cells of diabetic mice expressing CHOP suggests that continued induction of ER chaperones in these cells likely allows stress adaptive pathways to alleviate some stress in the chronic setting of diabetes and suppress pro-apoptotic pathways and stress-induced apoptosis (Rutkowski et al 2006;Wu et al 2007). Previously, no change in CHOP transcript levels was found in tubulointerstitial tissue from kidney biopsies of patients with established DN (Lindenmeyer et al 2008). Results of the current study suggest the possibility for increased CHOP protein stabilization, which occurs during stress (Rutkowski et al 2006).…”

“…Phosphorylation of PERK was higher in renal cortical tubules of younger diabetic mice suggesting adaptive mechanisms by tubule cells to ER stress-inducing stimuli, such as high glucose concentrations (Lindenmeyer et al 2008). Unaltered PERK phosphorylation in tubules of older (6-7-monthold) diabetic mice correlated with increased p58 IPK and suggests induction of negative feedback mechanisms and activation of the ATF-6 arm of ER stress response.…”

“…A previous study showed that high protein concentrations augment high glucose-induced GRP78 transcription in cultured proximal tubule cells (Lindenmeyer et al 2008). In the current study, CHOP was upregulated in tubules of older diabetic mice with severe proteinuria.…”

“…Early in diabetes, tubules undergo hypertrophy and expansion of the basement membrane and eventually atrophy and dilatation by the time DN is established (Hryciw et al 2004;Magri and Fava 2009;Thomas et al 2005). The presence of endoplasmic reticulum (ER) stress-response and ER stress-induced apoptotic markers has been shown in kidneys during diabetes (Brezniceanu et al 2010;Zhuang and Forbes 2014;Lindenmeyer et al 2008;Liu et al 2008;Wu et al 2010a, b). However, since the majority of the studies were conducted by analysis of markers in whole kidney homogenates, this stress response has not been clearly defined in different renal structures or tubule segments at different stages of diabetes.…”

Participation of endoplasmic reticulum stress in the pathogenesis of spontaneous glomerulosclerosis–Role of intra-renal angiotensin system

“…Hypertension and proteinuria have been shown to induce ER stress. 22,[44][45][46] Activation of Representative western blots and group data depicting the abundance of proteins mediating ER stressinduced apoptotic response (IRE1, ASK1, p-ASK1, p-Bcl2, BAX, and NFkB) in the control group and in the untreated Imai and ARB-treated Imai groups. n 5 6 in each group.…”