scholarly journals Mitochondria-Associated Endoplasmic Reticulum Membranes (MAMs) and Their Prospective Roles in Kidney Disease

2020 ◽  
Vol 2020 ◽  
pp. 1-21
Author(s):  
Peng Gao ◽  
Wenxia Yang ◽  
Lin Sun
Keyword(s):  
Quality Control ◽  
Endoplasmic Reticulum ◽  
Kidney Disease ◽  
Er Stress ◽  
Future Research ◽  
Inflammasome Activation ◽  
Mitochondrial Quality Control ◽  
Downstream Signaling ◽  
Contact Sites ◽  
Progression Of Kidney Disease

Mitochondria-associated endoplasmic reticulum (ER) membranes (MAMs) serve as essential hubs for interorganelle communication in eukaryotic cells and play multifunctional roles in various biological pathways. A defect in ER-mitochondria signaling or MAMs dysfunction has pleiotropic effects on a variety of intracellular events, which results in disturbances of the mitochondrial quality control system, Ca2+ dyshomeostasis, apoptosis, ER stress, and inflammasome activation, which all contribute to the onset and progression of kidney disease. Here, we review the structure and molecular compositions of MAMs as well as the experimental methods used to study these interorganellar contact sites. We will specifically summarize the downstream signaling pathways regulated by MAMs, mainly focusing on mitochondrial quality control, oxidative stress, ER-mitochondria Ca2+ crosstalk, apoptosis, inflammasome activation, and ER stress. Finally, we will discuss how alterations in MAMs integrity contribute to the pathogenesis of kidney disease and offer directions for future research.

scholarly journals Therapeutic Effect of Endothelin-Converting Enzyme Inhibitor on Chronic Kidney Disease through the Inhibition of Endoplasmic Reticulum Stress and the NLRP3 Inflammasome

Biomedicines ◽  
2021 ◽  
Vol 9 (4) ◽  
pp. 398
Author(s):  
Yung-Ho Hsu ◽  
Cai-Mei Zheng ◽  
Chu-Lin Chou ◽  
Yi-Jie Chen ◽  
Yu-Hsuan Lee ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Endoplasmic Reticulum ◽  
Kidney Disease ◽  
Epithelial Cells ◽  
Er Stress ◽  
Nlrp3 Inflammasome ◽  
Enzyme Inhibitor ◽  
Inflammasome Activation ◽  
Tubular Epithelial Cells ◽  
Domain 3

Chronic inflammation and oxidative stress significantly contribute to the development and progression of chronic kidney disease (CKD). The NOD-like receptor family pyrin containing domain-3 (NLRP3) inflammasome plays a key role in the inflammatory response. The renal endothelin (ET) system is activated in all cases of CKD. Furthermore, ET-1 promotes renal cellular injury, inflammation, fibrosis and proteinuria. Endothelin-converting enzymes (ECEs) facilitate the final processing step of ET synthesis. However, the roles of ECEs in CKD are not clear. In this study, we investigated the effects of ETs and ECEs on kidney cells. We found that ET-1 and ET-2 expression was significantly upregulated in the renal tissues of CKD patients. ET-1 and ET-2 showed no cytotoxicity on human kidney tubular epithelial cells. However, ET-1 and ET-2 caused endoplasmic reticulum (ER) stress and NLRP3 inflammasome activation in tubular epithelial cells. The ECE inhibitor phosphoramidon induced autophagy. Furthermore, phosphoramidon inhibited ER stress and the NLRP3 inflammasome in tubular epithelial cells. In an adenine diet-induced CKD mouse model, phosphoramidon attenuated the progression of CKD by regulating autophagy, the NLRP3 inflammasome and ER stress. In summary, these findings showed a new strategy to delay CKD progression by inhibiting ECEs through autophagy activation and restraining ER stress and the NLRP3 inflammasome.

scholarly journals Crosstalk between endoplasmic reticulum stress and oxidative stress: a dynamic duo in multiple myeloma

2021 ◽  
Author(s):  
Sinan Xiong ◽  
Wee-Joo Chng ◽  
Jianbiao Zhou
Keyword(s):  
Oxidative Stress ◽  
Multiple Myeloma ◽  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Cell Fate ◽  
Stress Responses ◽  
Plasma Cells ◽  
Reactive Oxygen Species Generation ◽  
Future Research ◽  
And Oxidative Stress

AbstractUnder physiological and pathological conditions, cells activate the unfolded protein response (UPR) to deal with the accumulation of unfolded or misfolded proteins in the endoplasmic reticulum. Multiple myeloma (MM) is a hematological malignancy arising from immunoglobulin-secreting plasma cells. MM cells are subject to continual ER stress and highly dependent on the UPR signaling activation due to overproduction of paraproteins. Mounting evidence suggests the close linkage between ER stress and oxidative stress, demonstrated by overlapping signaling pathways and inter-organelle communication pivotal to cell fate decision. Imbalance of intracellular homeostasis can lead to deranged control of cellular functions and engage apoptosis due to mutual activation between ER stress and reactive oxygen species generation through a self-perpetuating cycle. Here, we present accumulating evidence showing the interactive roles of redox homeostasis and proteostasis in MM pathogenesis and drug resistance, which would be helpful in elucidating the still underdefined molecular pathways linking ER stress and oxidative stress in MM. Lastly, we highlight future research directions in the development of anti-myeloma therapy, focusing particularly on targeting redox signaling and ER stress responses.

scholarly journals SGLT2 Inhibitors and Kidney Outcomes in Patients with Chronic Kidney Disease

2020 ◽  
Vol 9 (9) ◽  
pp. 2723 ◽  
Author(s):  
Swetha R. Kanduri ◽  
Karthik Kovvuru ◽  
Panupong Hansrivijit ◽  
Charat Thongprayoon ◽  
Saraschandra Vallabhajosyula ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Pressure Control ◽  
Future Research ◽  
Diabetic Patients ◽  
Special Focus ◽  
Combination Therapies ◽  
Positive Effects ◽  
Treatment Naïve ◽  
Progression Of Kidney Disease ◽  
End Stage

Globally, diabetes mellitus is a leading cause of kidney disease, with a critical percent of patients approaching end-stage kidney disease. In the current era, sodium-glucose co-transporter 2 inhibitors (SGLT2i) have emerged as phenomenal agents in halting the progression of kidney disease. Positive effects of SGLT2i are centered on multiple mechanisms, including glycosuric effects, tubule—glomerular feedback, antioxidant, anti-fibrotic, natriuretic, and reduction in cortical hypoxia, alteration in energy metabolism. Concurrently, multiple kidney and cardiovascular outcome studies have reported remarkable advantages of SGLT2i including mortality benefits. Additionally, the superiority of combination therapies (SGLT2I along with metformin/DDP-4 Inhibitors) in treatment-naïve diabetic patients is further looked into with potential signal towards glycemic and blood pressure control. Reported promising results initiate a gateway for future research targeting kidney outcomes with combination therapies as an initial approach. In the current paper, we summarize leading cardiovascular and kidney outcome trials in patients with type 2 diabetes, the role of SGLT2i in non-diabetic proteinuric kidney disease, and the potential mechanisms of action of SGLT2i with special focus on combination therapy as an initial therapeutic approach in treatment-naïve diabetic patients.

scholarly journals Activation of Mammalian Unfolded Protein Response Is Compatible with the Quality Control System Operating in the Endoplasmic Reticulum

2004 ◽  
Vol 15 (6) ◽  
pp. 2537-2548 ◽  
Author(s):  
Satomi Nadanaka ◽  
Hiderou Yoshida ◽  
Fumi Kano ◽  
Masayuki Murata ◽  
Kazutoshi Mori
Keyword(s):  
Quality Control ◽  
Endoplasmic Reticulum ◽  
Control System ◽  
Golgi Apparatus ◽  
Er Stress ◽  
Unfolded Protein Response ◽  
Secretory Pathway ◽  
Unfolded Proteins ◽  
Unfolded Protein ◽  
Protein Response

Newly synthesized secretory and transmembrane proteins are folded and assembled in the endoplasmic reticulum (ER) where an efficient quality control system operates so that only correctly folded molecules are allowed to move along the secretory pathway. The productive folding process in the ER has been thought to be supported by the unfolded protein response (UPR), which is activated by the accumulation of unfolded proteins in the ER. However, a dilemma has emerged; activation of ATF6, a key regulator of mammalian UPR, requires intracellular transport from the ER to the Golgi apparatus. This suggests that unfolded proteins might be leaked from the ER together with ATF6 in response to ER stress, exhibiting proteotoxicity in the secretory pathway. We show here that ATF6 and correctly folded proteins are transported to the Golgi apparatus via the same route and by the same mechanism under conditions of ER stress, whereas unfolded proteins are retained in the ER. Thus, activation of the UPR is compatible with the quality control in the ER and the ER possesses a remarkable ability to select proteins to be transported in mammalian cells in marked contrast to yeast cells, which actively utilize intracellular traffic to deal with unfolded proteins accumulated in the ER.

scholarly journals Organelle Stress and Crosstalk in Kidney Disease

Kidney360 ◽  
2020 ◽  
Vol 1 (10) ◽  
pp. 1155-1162
Author(s):  
Sho Hasegawa ◽  
Reiko Inagi
Keyword(s):  
Kidney Disease ◽  
Er Stress ◽  
Calcium Homeostasis ◽  
Stress Responses ◽  
Primary Cilia ◽  
Proximal Tubular Cells ◽  
Cellular Homeostasis ◽  
Tubular Cells ◽  
Progression Of Kidney Disease ◽  
Proximal Tubular

Organelles play important roles in maintaining cellular homeostasis. Organelle stress responses, especially in mitochondria, endoplasmic reticula (ER), and primary cilia, are deeply involved in kidney disease pathophysiology. Mitochondria are the center of energy production in most eukaryotic cells. Renal proximal tubular cells are highly energy demanding and abundant in mitochondria. Mitochondrial dysfunctions in association with energy metabolism alterations produce reactive oxygen species and promote inflammation in proximal tubular cells, resulting in progression of kidney disease. The ER play critical roles in controlling protein quality. Unfolded protein response (UPR) pathways are the adaptive response to ER stress for maintaining protein homeostasis. UPR pathway dysregulation under pathogenic ER stress often occurs in glomerular and tubulointerstitial cells and promotes progression of kidney disease. The primary cilia sense extracellular signals and maintain calcium homeostasis in cells. Dysfunction of the primary cilia in autosomal dominant polycystic kidney disease reduces the calcium concentration in proximal tubular cells, leading to increased cell proliferation and retention of cyst fluid. In recent years, the direct interaction at membrane contact sites has received increased attention in association with the development of imaging technologies. The part of the ER that is directly connected to mitochondria is termed the mitochondria-associated ER membrane (MAM), which regulates calcium homeostasis and phospholipid metabolism in cells. Disruption of MAM integrity collapses cellular homeostasis and leads to diseases such as diabetes and Alzheimer disease. This review summarizes recent research on organelle stress and crosstalk, and their involvement in kidney disease pathophysiology. In addition, potential treatment options that target organelle stress responses are discussed.

scholarly journals The Loss of Mitochondrial Quality Control in Diabetic Kidney Disease

2021 ◽  
Vol 9 ◽  
Author(s):  
Wenni Dai ◽  
Hengcheng Lu ◽  
Yinyin Chen ◽  
Danyi Yang ◽  
Lin Sun ◽  
...  
Keyword(s):  
Quality Control ◽  
Kidney Disease ◽  
Diabetic Kidney Disease ◽  
Protein Quality ◽  
Current Knowledge ◽  
Mitochondrial Dynamics ◽  
Mitochondrial Protein ◽  
Eukaryotic Cell ◽  
Mitochondrial Quality Control ◽  
Diabetic Kidney

Diabetic kidney disease (DKD) is the predominant complication of diabetes mellitus (DM) and the leading cause of chronic kidney disease and end-stage renal disease worldwide, which are major risk factors for death. The pathogenesis of DKD is very complicated, including inflammation, autophagy impairment, oxidative stress, and so on. Recently, accumulating evidence suggests that the loss of mitochondrial quality control exerts critical roles in the progression of DKD. Mitochondria are essential for eukaryotic cell viability but are extremely vulnerable to damage. The mechanisms of mitochondrial quality control act at the molecular level and the organelle level, including mitochondrial dynamics (fusion and fission), mitophagy, mitochondrial biogenesis, and mitochondrial protein quality control. In this review, we summarize current knowledge of the role of disturbances in mitochondrial quality control in the pathogenesis of DKD and provide potential insights to explore how to delay the onset and development of DKD.

scholarly journals The Role of Posttranslational Modification and Mitochondrial Quality Control in Cardiovascular Diseases

2021 ◽  
Vol 2021 ◽  
pp. 1-15
Author(s):  
Jinlin Liu ◽  
Li Zhong ◽  
Rui Guo
Keyword(s):  
Quality Control ◽  
Posttranslational Modifications ◽  
Posttranslational Modification ◽  
Protein Function ◽  
Therapeutic Potential ◽  
Normal Function ◽  
Future Research ◽  
Mitochondrial Quality Control ◽  
Mitochondrial Homeostasis

Cardiovascular disease (CVD) is the leading cause of death in the world. The mechanism behind CVDs has been studied for decades; however, the pathogenesis is still controversial. Mitochondrial homeostasis plays an essential role in maintaining the normal function of the cardiovascular system. The alterations of any protein function in mitochondria may induce abnormal mitochondrial quality control and unexpected mitochondrial dysfunction, leading to CVDs. Posttranslational modifications (PTMs) affect protein function by reversibly changing their conformation. This review summarizes how common and novel PTMs influence the development of CVDs by regulating mitochondrial quality control. It provides not only ideas for future research on the mechanism of some types of CVDs but also ideas for CVD treatments with therapeutic potential.

scholarly journals The interaction of S100A16 and GRP78 actives endoplasmic reticulum stress-mediated through the IRE1α/XBP1 pathway in renal tubulointerstitial fibrosis

2021 ◽  
Vol 12 (10) ◽  
Author(s):  
Runbing Jin ◽  
Anran Zhao ◽  
Shuying Han ◽  
Dan Zhang ◽  
Hui Sun ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Kidney Disease ◽  
Er Stress ◽  
Calcium Binding ◽  
Renal Fibrosis ◽  
Physical Interaction ◽  
Stress Markers ◽  
Protein Partner ◽  
Renal Tubulointerstitial Fibrosis ◽  
Ureteral Occlusion

AbstractRecent studies have indicated that the development of acute and chronic kidney disease including renal fibrosis is associated with endoplasmic reticulum (ER) stress. S100 calcium-binding protein 16 (S100A16) as a novel member of the S100 family is involved in kidney disease; however, few studies have examined fibrotic kidneys for a relationship between S100A16 and ER stress. In our previous study, we identified GRP78 as a protein partner of S100A16 in HK-2 cells. Here, we confirmed a physical interaction between GRP78 and S100A16 in HK-2 cells and a markedly increased expression of GRP78 in the kidneys of unilateral ureteral occlusion mice. S100A16 overexpression in HK-2 cells by infection with Lenti-S100A16 also induced upregulation of ER stress markers, including GRP78, p-IRE1α, and XBP1s. Immunofluorescence staining demonstrated that the interaction between S100A16 and GRP78 predominantly occurred in the ER of control HK-2 cells. By contrast, HK-2 cells overexpressing S100A16 showed colocalization of S100A16 and GRP78 mainly in the cytoplasm. Pretreatment with BAPTA-AM, a calcium chelator, blunted the upregulation of renal fibrosis genes and ER stress markers induced by S100A16 overexpression in HK-2 cells and suppressed the cytoplasmic colocalization of GRP78 and S100A16. Co-immunoprecipitation studies suggested a competitive binding between S100A16 and IRE1α with GRP78 in HK-2 cells. Taken together, our findings demonstrate a significant increase in S100A16 expression in the cytoplasm following renal injury. GRP78 then moves into the cytoplasm and binds with S100A16 to promote the release of IRE1α. The subsequent phosphorylation of IRE1α then leads to XBP1 splicing that activates ER stress.

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