Is the ER Stressed out in Diabetic Kidney Disease?
Authors: Frank C. Brosius, Randal J. Kaufman
Journal: Journal of the American Society of Nephrology (2008)

Despite decades of concerted mechanistic research, the pathogenesis of progressive diabetic nephropathy remains uncertain. Although improved glycemic control and treatment with angiotensin-converting enzyme inhibitors or angiotensin receptor blockers ameliorate the progression of diabetic nephropathy to end-stage kidney disease, the mechanisms for such salutary effects have not been clearly identified and are likely myriad. Moreover, these interventions do not forestall progression of disease, at least in the majority of sufferers, but merely retard it. Thus, new insights into the mechanisms of this disease will be critical so that additional and more effective therapies can be discovered. In this issue of JASN, Cohen and Schlo[Combining Diaeresis]ndorff and colleagues1 provide such an insight by demonstrating the induction of a number of genes that are involved in endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) in tubulointerstitial cells of kidney biopsies from humans with progressive diabetic nephropathy compared with similar regions from normal individuals and those with early diabetic nephropathy or minimal-change disease. ER stress is caused by any physiologic, pathophysiologic, or pharmacologic stimulus that increases the demands on the ER to synthesize proteins or degrade improperly folded proteins. These stimuli trigger the UPR, which reduces the amount of nascent protein that enters the ER lumen, increases ER capacity to fold protein through enhanced transcription of genes of ER chaperones and folding catalysts, and induces degradation of misfolded and aggregated proteins.2 With massive ER stress, these prosurvival aspects of the UPR can be superseded by proapoptotic aspects, leading to programmed cell death.2 In their article in this issue, the investigators demonstrate increased expression of several genes for protective ER chaperone proteins as well as increased expression of a prosurvival gene for a basic leucine zipper-containing transcription factor X-box binding protein 1 (XBP1) in tubulointerstitial cells in two independent sets of patients with progressive diabetic nephropathy. In contrast, they found no induction or even suppression of genes for proapoptotic features of the UPR. Although there have been several previous reports of induction of UPR in podocytes and other kidney cells by high glucose, albumin, or other compounds found in diabetic plasma and glomerular filtrate,3–5 the article by Cohen and Scho[Combining Diaeresis]ndorff and colleagues1 is the first to show induction of UPR genes in human diabetic nephropathy. That ER stress is responsible for diabetic injury is not a new concept. A plethora of reports show that high glucose and free fatty acids in patients with diabetes can induce ER stress and UPR gene induction in pancreatic β cells (for recent reviews see references2,6–12). The β cell is particularly susceptible to ER stress because it makes nearly 1 million proinsulin molecules per minute2 and any increase in this demand, such as with insulin resistance, can lead to accumulation of unfolded protein and cause β cell failure and frank type 2 diabetes. In a similar vein, diabetes triggers ER stress and the UPR in proximal tubular cells as a result of exposure to high glucose, free fatty acids, and other features of the diabetic milieu. Because induction of the same genes was much less dramatic in minimal-change disease, it is likely that a combination of factors in addition to exposure to filtered proteins is responsible. The investigators found that a combination of elevated albumin and glucose levels induce some of the same UPR genes in cultured proximal tubular cell lines that were enhanced in vivo. The substantial augmentation of oxidative stress in diabetic tubuli is one likely responsible factor for these effects.13 Oxidative stress clearly induces ER stress and vice versa.14 Indeed, ER stress can induce oxidative stress in pancreatic β cells, and a similar process may contribute to enhanced oxidative stress in diabetic nephropathy.15 The finding of increased mRNA levels for genes involved in the protective responses of the UPR but not for proapoptotic genes suggests that the ER stress found in the tubulointerstitial cells in these patients with progressive diabetic nephropathy is adaptive and sustainable. Indeed, physiologic activation of the UPR often selectively enhances the prosurvival aspects of the response.16 This pattern is consistent with adaptive versus terminal UPR activation and seems to result from selective instability of proapoptotic mRNA and proteins during prolonged but survivable ER stress.16 This observation begs the question of whether sustainable UPR would result in worsening diabetic nephropathy. In fact, the induction of the UPR in these patients seems most likely to be a marker of an adaptive and protective response to ER stress and therefore not directly involved in the progression of diabetic nephropathy in these individuals. Although the authors acknowledge this possibility, they clearly expect that prolonged ER stress in diabetes in vivo could ultimately be responsible for tubular cell damage through processes of the terminal UPR; however, there is nothing in their report that substantiates this notion. Indeed, the patients with progressive diabetic nephropathy already had sustained substantial tubulointerstitial damage and significant declines in renal function without any evidence of induction of proapoptotic components of the UPR. This strongly suggests that diabetic damage took place independent of any terminal UPR process. Moreover, only a handful of UPR genes are regulated in the tubulointerstitial cells of these patients, whereas most of the genes for UPR proteins are unaffected, with many of the known UPR genes below the level of significant detection. Finally, it would have been relatively easy to determine the extent of XBP1 mRNA splicing at the time the reverse transcription–PCR experiments were performed. XBP1 splicing, a proximal event in the activation of the UPR sensor IRE1, is a more sensitive indicator of ER stress than the gene expression changes reported by the authors. Certainly, therefore, further investigation is necessary to help define the nature of the relationship between progressive diabetic nephropathy and the UPR. Despite these concerns, the authors are to be applauded for identifying these responses in humans with sophisticated gene expression tools. This study, as well as dozens of others, has been made possible by the prescient formation and careful maintenance of the European Renal cDNA Bank (ERCB), which has now catalogued nearly 2500 renal biopsies from individuals with a broad spectrum of kidney diseases, including diabetic nephropathy. Critically, detailed clinical information as well as biopsy material is available for each patient in a standardized and extensively validated manner, which allows studies based on this material to be truly authoritative.17,18 This consortial effort is now truly worldwide with contributions and collaborators from North America, Australia, and Asia as well as from Europe. It is no exaggeration to state that this effort has resulted in seminal new insights into the etiology, pathogenesis, and classification of many kidney diseases, including diabetic nephropathy,19–20 and it will certainly continue to be a major driving force behind the nephrology community's efforts to reclassify renal diseases on a truly molecular basis. Although this is the first report on the role of ER stress in diabetic nephropathy from ERCB investigators, it will certainly not be the last. DISCLOSURES R.J.K. is an investigator of the Howard Hughes Medical Institute.