scholarly journals P0719SRC KINASES AGGRAVATE DIABETIC KIDNEY INJURY THROUGH ACTIVATION OF ENDOPLASMIC RETICULUM STRESS

2020 ◽  
Vol 35 (Supplement_3) ◽  
Author(s):  
Debra Dorotea ◽  
Hunjoo Ha
Keyword(s):  
Endoplasmic Reticulum ◽  
Kidney Disease ◽  
Er Stress ◽  
Kidney Injury ◽  
Diabetic Rats ◽  
Src Kinases ◽  
Mrna Levels ◽  
Diabetic Kidney ◽  
Kidney Fibrosis ◽  
In The Diabetic Kidney

Abstract Background and Aims Diabetic kidney disease (DKD) is the major cause of end-stage kidney disease which is characterized by prominent kidney fibrosis. Src family kinases (SFKs), a family of proto-oncogenes, has been acknowledged to mediate the development of kidney fibrosis. While, several studies in liver and skeletal muscle suggested the role of Src kinases in activating endoplasmic reticulum (ER) stress. The present study aimed to investigate the mechanism of Src kinases-ER stress in mediating the progression of DKD. Method Type 1 diabetes was induced by a single 60 mg/kg i.p injection of streptozotocin (STZ) in 7-week-old male, Sprague-Dawley rats. Diabetic rats received 8-week-treatment of either KF-1607 (30 mg/kg/day), a pharmacological inhibitor of SFKs, or losartan (1 mg/kg/day), a standard treatment for patients with DKD. Results Among SFKs, Fyn and Lyn kinases were particularly increased in the diabetic kidney. Inhibition of Src kinases by KF-1607 improved kidney function and inhibited tubular injury, presented by decreased serum creatinine, albuminuria, and urinary KIM-1 excretion. Pathological changes in the kidney, such as enhanced glomerular volume, tuft area, and fractional mesangial area, were ameliorated in KF-treated rats. Highly-accumulated collagen network as well as increased TGF-β and α-SMA mRNA levels in the diabetic kidney were also significantly reduced in response to KF treatment. Furthermore, it consistently attenuated kidney inflammation and oxidative stress. The renoprotective effects of KF were interestingly similar to those of losartan. We showed increases in protein levels of phosphorylated IRE-1α, ATF6, GRP78 as well as CHOP indicating an exacerbated ER stress in the diabetic kidney. These ER stress markers were significantly decreased in KF treated mice. Conclusion Altogether, Src kinases through activation of ER stress aggravates kidney injury in STZ-induced diabetic rats.

scholarly journals Cigarette smoke inhalation aggravates diabetic kidney injury in rats

2019 ◽  
Vol 8 (6) ◽  
pp. 964-971 ◽  
Author(s):  
Songling Jiang ◽  
Do Van Quan ◽  
Jae Hyuck Sung ◽  
Moo-Yeol Lee ◽  
Hunjoo Ha
Keyword(s):  
Kidney Disease ◽  
Cigarette Smoke ◽  
Density Lipoprotein ◽  
Kidney Injury ◽  
Diabetic Rats ◽  
Smoke Inhalation ◽  
Lipoprotein Cholesterol ◽  
Sprague Dawley ◽  
Experimental Conditions ◽  
Diabetic Kidney

Abstract Diabetic kidney disease (DKD) is the leading cause of end-stage kidney disease. Epidemiological studies have demonstrated that cigarette smoke or nicotine is a risk factor for the progression of chronic kidney injury. The present study analyzed the kidney toxicity of cigarette smoke in experimental rats with DKD. Experimental diabetes was induced in 7-week-old Sprague-Dawley rats by a single intraperitoneal injection of streptozotocin (60 mg kg−1). Four weeks after the induction of diabetes, rats were exposed to cigarette smoke (200 μg L−1), 4 h daily, and 5 days per week for 4 weeks. Cigarette smoke did not affect the levels of plasma glucose, hemoglobin A1c, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol or non-esterified fatty acids in both control and diabetic rats under the experimental conditions. Cigarette smoke, however, significantly increased diabetes-induced glomerular hypertrophy and urinary kidney injury molecule-1 (KIM-1) and neutrophil gelatinase-associated lipocalin (NGAL) excretion, suggesting exacerbation of diabetic kidney injury. Cigarette smoke promoted macrophage infiltration and fibrosis in the diabetic kidney. As expected, cigarette smoke increased oxidative stress in both control and diabetic rats. These data demonstrated that four weeks of exposure to cigarette smoke aggravated the progression of DKD in rats.

scholarly journals Sodium Bicarbonate Supplementation and Urinary TGF-β1 in Nonacidotic Diabetic Kidney Disease

2020 ◽  
Vol 15 (2) ◽  
pp. 200-208 ◽  
Author(s):  
Kalani L. Raphael ◽  
Tom Greene ◽  
Guo Wei ◽  
Tristin Bullshoe ◽  
Kunani Tuttle ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Sodium Bicarbonate ◽  
Diabetic Kidney Disease ◽  
Kidney Injury ◽  
Normal Serum ◽  
Controlled Study ◽  
Ammonium Excretion ◽  
Diabetic Kidney ◽  
Kidney Fibrosis ◽  
Titratable Acid

Background and objectivesIn early-phase studies of individuals with hypertensive CKD and normal serum total CO2, sodium bicarbonate reduced urinary TGF-β1 levels and preserved kidney function. The effect of sodium bicarbonate on kidney fibrosis and injury markers in individuals with diabetic kidney disease and normal serum total CO2 is unknown.Design, setting, participants, & measurementsWe conducted a randomized, double-blinded, placebo-controlled study in 74 United States veterans with type 1 or 2 diabetes mellitus, eGFR of 15–89 ml/min per 1.73 m2, urinary albumin-to-creatinine ratio (UACR) ≥30 mg/g, and serum total CO2 of 22–28 meq/L. Participants received oral sodium bicarbonate (0.5 meq/kg lean body wt per day; n=35) or placebo (n=39) for 6 months. The primary outcome was change in urinary TGF-β1-to-creatinine from baseline to months 3 and 6. Secondary outcomes included changes in urinary kidney injury molecule-1 (KIM-1)-to-creatinine, fibronectin-to-creatinine, neutrophil gelatinase-associated lipocalin (NGAL)-to-creatinine, and UACR from baseline to months 3 and 6.ResultsKey baseline characteristics were age 72±8 years, eGFR of 51±18 ml/min per 1.73 m2, and serum total CO2 of 24±2 meq/L. Sodium bicarbonate treatment increased mean total CO2 by 1.2 (95% confidence interval [95% CI], 0.3 to 2.1) meq/L, increased urinary pH by 0.6 (95% CI, 0.5 to 0.8), and decreased urinary ammonium excretion by 5 (95% CI, 0 to 11) meq/d and urinary titratable acid excretion by 11 (95% CI, 5 to 18) meq/d. Sodium bicarbonate did not significantly change urinary TGF-β1/creatinine (difference in change, 13%, 95% CI, −10% to 40%; change within the sodium bicarbonate group, 8%, 95% CI, −10% to 28%; change within the placebo group, −4%, 95% CI, −19% to 13%). Similarly, no significant effect on KIM-1-to-creatinine (difference in change, −10%, 95% CI, −38% to 31%), fibronectin-to-creatinine (8%, 95% CI, −15% to 37%), NGAL-to-creatinine (−33%, 95% CI, −56% to 4%), or UACR (1%, 95% CI, −25% to 36%) was observed.ConclusionsIn nonacidotic diabetic kidney disease, sodium bicarbonate did not significantly reduce urinary TGF-β1, KIM-1, fibronectin, NGAL, or UACR over 6 months.

scholarly journals Renoprotective Effect of the Shen-Yan-Fang-Shuai Formula by Inhibiting TNF-α/NF-κB Signaling Pathway in Diabetic Rats

2017 ◽  
Vol 2017 ◽  
pp. 1-11 ◽  
Author(s):  
Jie Lv ◽  
Zhen Wang ◽  
Ying Wang ◽  
Weiwei Sun ◽  
Jingwei Zhou ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Signaling Pathway ◽  
Molecular Mechanisms ◽  
Mesangial Cells ◽  
Kidney Injury ◽  
Treated Group ◽  
Diabetic Rats ◽  
Diabetic Rat ◽  
Diabetic Kidney ◽  
End Stage

Diabetic kidney disease (DKD) is the leading cause of end-stage kidney disease, and satisfactory therapeutic strategies have not yet been established. The Shen-Yan-Fang-Shuai Formula (SYFSF) is a traditional Chinese formula composed of Astragali radix, Radixangelicae sinensis, Rheum officinale Baill, and four other herbs. It has been widely used as an effective treatment for DKD patients in China. However, little is known about the molecular mechanisms underlying SYFSF’s renoprotection. In this study, we compared the protective effect of SYFSF to irbesartan on the histology and renal cells in type 2 DKD rat model and high-glucose (HG) cultured mesangial cells, respectively. We found that SYFSF could significantly decrease urinary albumin, cholesterol, and triglyceride. And a decrease in serum creatinine was also found in SYFSF-treated group compared with irbesartan-treated rats. In addition, SYFSF inhibited the interstitial expansion and glomerulosclerosis in diabetic rats. Notably, SYFSF markedly downregulated the expression of MCP-1, TGF-β1, collagen IV, and fibronectin in diabetic rat models and HG-induced mesangial cell models. The renoprotection was closely associated with a reduced expression of TNF-α and phosphorylated NF-κBp65. Our study suggests that SYFSF may ameliorate diabetic kidney injury. The observed renoprotection is probably attributable to an inhibition of inflammatory response and extracellular matrix (ECM) accumulation mediated by TNF-α/NF-κBp65 signaling pathway.

scholarly journals The endoplasmic reticulum stress response and diabetic kidney disease

2011 ◽  
Vol 300 (5) ◽  
pp. F1054-F1061 ◽  
Author(s):  
Robyn Cunard ◽  
Kumar Sharma
Keyword(s):  
Endoplasmic Reticulum ◽  
Stress Response ◽  
Kidney Disease ◽  
Er Stress ◽  
Diabetic Kidney Disease ◽  
Protein Translation ◽  
Renal Diseases ◽  
Unfolded Proteins ◽  
Diabetic Kidney ◽  
Er Stress Response

The endoplasmic reticulum (ER) folds and modifies proteins; however, during conditions of cellular stress, unfolded proteins accumulate in the ER and activate the unfolded protein response (UPR). The UPR, also referred to as the ER stress response, activates three distinct signaling cascades that are designed to globally reduce transcription and translation. The three major arms of the mammalian UPR include 1) protein kinase RNA (PKR)-like ER kinase (PERK), 2) inositol-requiring protein-1 (IRE1α), and 3) activating transcription factor-6 (ATF6) pathways. The PERK pathway rapidly attenuates protein translation, whereas the ATF6 and IRE1α cascades transcriptionally upregulate ER chaperone genes that promote proper folding and ER-associated degradation (ERAD) of proteins. This integrated response in turn allows the folding machinery of the ER to catch up with the backlog of unfolded proteins. The ER stress response plays a role in a number of pathophysiological processes, including pancreatic β-cell failure and apoptosis. The goals of the current review are to familiarize investigators with cellular and tissue activation of this response in the rodent and human diabetic kidney. Additionally, we will review therapeutic modulators of the ER stress response and discuss their efficacy in models of diabetic kidney disease. The ER stress response has both protective and deleterious features. A better understanding of the molecular pathways regulated during this process in a cell- and disease-specific manner could reveal novel therapeutic strategies in chronic renal diseases, including diabetic kidney disease.

scholarly journals Recent Advances in Diabetic Kidney Diseases: From Kidney Injury to Kidney Fibrosis

2021 ◽  
Vol 22 (21) ◽  
pp. 11857
Author(s):  
Peir-Haur Hung ◽  
Yung-Chien Hsu ◽  
Tsung-Hsien Chen ◽  
Chun-Liang Lin
Keyword(s):  
Kidney Disease ◽  
Kidney Diseases ◽  
Epigenetic Modification ◽  
Kidney Injury ◽  
Diabetic Kidney ◽  
Kidney Fibrosis ◽  
Recent Advances ◽  
History Of ◽  
Stage Renal Disease ◽  
End Stage

Diabetic kidney disease (DKD) is the leading cause of chronic kidney disease and end-stage renal disease. The natural history of DKD includes glomerular hyperfiltration, progressive albuminuria, declining estimated glomerular filtration rate, and, ultimately, kidney failure. It is known that DKD is associated with metabolic changes caused by hyperglycemia, resulting in glomerular hypertrophy, glomerulosclerosis, and tubulointerstitial inflammation and fibrosis. Hyperglycemia is also known to cause programmed epigenetic modification. However, the detailed mechanisms involved in the onset and progression of DKD remain elusive. In this review, we discuss recent advances regarding the pathogenic mechanisms involved in DKD.

Testicular Injury Attenuated by Rapamycin Through Induction of Autophagy and Inhibition of Endoplasmic Reticulum Stress in Streptozotocin- Induced Diabetic Rats

2019 ◽  
Vol 19 (5) ◽  
pp. 665-675 ◽  
Author(s):  
Wenjiao Shi ◽  
Zhixin Guo ◽  
Ruixia Yuan
Keyword(s):  
Oxidative Stress ◽  
Endoplasmic Reticulum ◽  
Endoplasmic Reticulum Stress ◽  
Protective Effect ◽  
Er Stress ◽  
B Cell Lymphoma ◽  
Diabetic Rats ◽  
Pathological Changes ◽  
Rapamycin Treatment ◽  
Related Proteins

Background and Objective: This study investigated whether rapamycin has a protective effect on the testis of diabetic rats by regulating autophagy, endoplasmic reticulum stress, and oxidative stress. Methods: Thirty male Sprague-Dawley rats were randomly divided into three groups: control, diabetic, and diabetic treated with rapamycin, which received gavage of rapamycin (2mg.kg-1.d-1) after induction of diabetes. Diabetic rats were induced by intraperitoneal injection of streptozotocin (STZ, 65mg.Kg-1). All rats were sacrificed at the termination after 8 weeks of rapamycin treatment. The testicular pathological changes were determined by hematoxylin and eosin staining. The protein or mRNA expression of autophagy-related proteins (Beclin1, microtubule-associated protein light chain 3 (LC3), p62), ER stress marked proteins (CCAAT/enhancer-binding protein (C/EBP) homologous protein (CHOP), caspase-12), oxidative stress-related proteins (p22phox, nuclear factor erythroid2-related factor 2 (Nrf2)) and apoptosis-related proteins (Bax, B cell lymphoma-2 (Bcl-2)) were assayed by western blot or real-time fluorescence quantitative PCR. Results: There were significant pathological changes in the testes of diabetic rats. The expression of Beclin1, LC3, Nrf2, Bcl-2 were significantly decreased and p62, CHOP, caspase12, p22phox, and Bax were notably increased in the testis of diabetic rats (P <0.05). However, rapamycin treatment for 8 weeks significantly reversed the above changes in the testis of diabetic rats (P <0.05). Conclusion: Rapamycin appears to produce a protective effect on the testes of diabetic rats by inducing the expression of autophagy and inhibiting the expression of ER-stress, oxidative stress, and apoptosis.

scholarly journals Cellular Mechanisms of Tissue Fibrosis. 3. Novel mechanisms of kidney fibrosis

2013 ◽  
Vol 304 (7) ◽  
pp. C591-C603 ◽  
Author(s):  
Gabriela Campanholle ◽  
Giovanni Ligresti ◽  
Sina A. Gharib ◽  
Jeremy S. Duffield
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Interstitial Fibrosis ◽  
Kidney Injury ◽  
Innate Immune ◽  
Cellular Mechanisms ◽  
Tubular Atrophy ◽  
Kidney Fibrosis ◽  
Capillary Rarefaction ◽  
Peritubular Capillaries

Chronic kidney disease, defined as loss of kidney function for more than three months, is characterized pathologically by glomerulosclerosis, interstitial fibrosis, tubular atrophy, peritubular capillary rarefaction, and inflammation. Recent studies have identified a previously poorly appreciated, yet extensive population of mesenchymal cells, called either pericytes when attached to peritubular capillaries or resident fibroblasts when embedded in matrix, as the progenitors of scar-forming cells known as myofibroblasts. In response to sustained kidney injury, pericytes detach from the vasculature and differentiate into myofibroblasts, a process not only causing fibrosis, but also directly contributing to capillary rarefaction and inflammation. The interrelationship of these three detrimental processes makes myofibroblasts and their pericyte progenitors an attractive target in chronic kidney disease. In this review, we describe current understanding of the mechanisms of pericyte-to-myofibroblast differentiation during chronic kidney disease, draw parallels with disease processes in the glomerulus, and highlight promising new therapeutic strategies that target pericytes or myofibroblasts. In addition, we describe the critical paracrine roles of epithelial, endothelial, and innate immune cells in the fibrogenic process.

PERK mediates oxidative stress and adipogenesis in Graves’ orbitopathy pathogenesis

2021 ◽  
Author(s):  
JaeSang Ko ◽  
Ji-Young Kim ◽  
Min Kyung Chae ◽  
Eun Jig Lee ◽  
Jin Sook Yoon
Keyword(s):  
Oxidative Stress ◽  
Hydrogen Peroxide ◽  
Endoplasmic Reticulum ◽  
Transcription Factor ◽  
Er Stress ◽  
Adipogenic Differentiation ◽  
Ros Generation ◽  
Mrna Levels ◽  
Graves Orbitopathy ◽  
Orbital Fibroblasts

We examined endoplasmic reticulum (ER) stress-related gene expression in orbital tissues from patients with Graves’ orbitopathy (GO) and the effects of silencing protein kinase RNA-like endoplasmic reticulum kinase (PERK) in primary orbital fibroblast cultures to demonstrate the therapeutic potential of PERK-modulating agents in GO management. The expression of ER stress related genes in orbital tissue harvested from individuals with or without GO was studied using real-time polymerase chain reaction. The role of PERK in GO pathogenesis was examined through small-interfering RNA (siRNA)-mediated silencing in cultured primary orbital fibroblasts. Intracellular reactive oxygen species (ROS) levels induced in response to cigarette smoke extract (CSE) or hydrogen peroxide were measured using 5-(and 6)-carboxy-20,70-dichlorodihydrofluorescein diacetate staining and flow cytometry. Cells were stained with Oil Red O, and adipogenesis-related transcription factor expression was evaluated through western blotting after adipogenic differentiation. PERK, activating transcription factor 4 (ATF4), and CCAAT-enhancer-binding protein (C/EBP)-homologous protein(CHOP)mRNA levels were significantly higher in GO orbital tissues than in non-GO orbital tissues. PERK silencing inhibited CSE- or hydrogen peroxide-induced ROS generation. After adipogenic differentiation, GO orbital fibroblasts revealed decreased lipid droplets and downregulation of C/EBPα, C/EBPβ, and peroxisome proliferator-activator gamma (PPARγ) in PERK siRNA-transfected cells. The orbital tissues of patients with GO were exposed to chronic ER stress and subsequently exhibited enhanced unfolded protein response (especially through the PERK pathway). PERK silencing reduced oxidative stress and adipogenesis in GO orbital fibroblasts in vitro. Our results imply that PERK-modulating agents can potentially be used to manage GO.

Abstract 016: Profound and Sustained Amplification of Circulating ACE2 Activity Does Not Protect Diabetic Mice from Kidney Disease

Hypertension ◽  
2015 ◽  
Vol 66 (suppl_1) ◽  
Author(s):  
Jan Wysocki ◽  
Minghao Ye ◽  
Ahmed M Khattab ◽  
Yashpal Kanwar ◽  
Mark Osborn ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Diabetic Kidney Disease ◽  
Kidney Injury ◽  
Renin Angiotensin System ◽  
Diabetic Mice ◽  
Diabetic Kidney ◽  
Over Expression ◽  
Akita Mice

ACE2 is a monocarboxypeptidase that by converting AngII to Ang1-7 should down-regulate the renin-angiotensin system and therefore provide a means to therapeutically target diabetic kidney disease, a condition where the kidney RAS is overactive. Previous work indicated that soluble human recombinant (r)ACE2 administration for 4 weeks attenuated kidney injury in diabetic Akita mice. Whether such effect of rACE2 can be confirmed and attributed to augmented ACE2 activity is uncertain because chronic use of human rACE2 in mice induces immunogenicity and the development of antibodies that neutralize serum ACE2 activity. To examine the effect of chronic amplification of circulating ACE2 on kidney injury caused by STZ-induced diabetes and to circumvent the immunogenicity arising from xenogeneic ACE2, ACE2 of mouse origin was administered to mice using either daily i.p. injections (1 mg/kg) of mrACE2 for 4 weeks or after 20 weeks of ACE2 mini-circle (MC) (10-30ug/mouse) administration. MC provides a form of gene delivery that is resistant to gene silencing and, in addition, greatly optimizes long-term in vivo overexpression of proteins of interest. ACE2MC resulted in a profound and sustained increase in serum ACE2 activity (2.4±0.3 vs. 497±135 RFU/ul/hr, p<0.01) but kidney ACE2 activity was unchanged (17.4±1.3 vs. 19.0±0.8 RFU/ug prot/hr). mACE2-treated mice injected with STZ developed diabetes similar to sham mice injected with STZ. Systolic BP was not different between non-diabetic mice, sham STZ-mice, and STZ-mice receiving mACE2 by either i.p. mrACE2 or ACE2MC. Urinary albumin was similarly increased in sham STZ-mice and in STZ-mice receiving mACE2. Glomerular mesangial score and glomerular cellularity were both increased to a similar extent in sham STZ-mice and in STZ-mice with mACE2 administration, as compared to non-diabetic controls. In conclusion, profound and long-term augmentation of ACE2 activity confined to the circulation is not sufficient to attenuate glomerular pathology and albuminuria in STZ-induced diabetic kidney disease probably because of lack of kidney delivery of ACE2. Strategies to achieve over-expression of ACE2 at the kidney level are needed to demonstrate a beneficial effect of this enzyme on diabetic kidney disease.

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