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Pathogenesis diabetic nephropathy

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https://www.readbyqxmd.com/read/28646406/podocytes-and-the-quest-for-precision-medicines-for-kidney-diseases
#1
REVIEW
Peter Mundel
In this review, I describe a 30-year journey in the quest for precision medicines for patients with kidney diseases. In 1987, when I started my reseach career, most scientists studying glomerular disease biology were focused on mesangial cells. The crucial role of the podocyte in many kidney diseases characterized by proteinuria, including focal segmental glomerulosclerosis (FSGS) and diabetic nephropathy, had not yet been recognized. We were not aware of genetic causes or drivers of kidney diseases nor of molecular markers and cell culture systems for mechanistic studies of podocyte biology...
June 23, 2017: Pflügers Archiv: European Journal of Physiology
https://www.readbyqxmd.com/read/28643424/mdm2-is-implicated-in-high-glucose-induced-podocyte-mitotic-catastrophe-via-notch1-signalling
#2
Hui Tang, Chun-Tao Lei, Chen Ye, Pan Gao, Cheng Wan, Shan Chen, Fang-Fang He, Yu-Mei Wang, Hua Su, Chun Zhang
Podocyte injury and depletion are essential events involved in the pathogenesis of diabetic nephropathy (DN). As a terminally differentiated cell, podocyte is restricted in 'post-mitosis' state and unable to regenerate. Re-entering mitotic phase will cause podocyte disastrous death which is defined as mitotic catastrophe (MC). Murine double minute 2 (MDM2), a cell cycle regulator, is widely expressed in renal resident cells including podocytes. Here, we explore whether MDM2 is involved in podocyte MC during hyperglycaemia...
June 23, 2017: Journal of Cellular and Molecular Medicine
https://www.readbyqxmd.com/read/28637012/infiltrating-macrophages-in-diabetic-nephropathy-promote-podocytes-apoptosis-via-tnf-%C3%AE-ros-p38mapk-pathway
#3
Yinfeng Guo, Zhixia Song, Min Zhou, Ying Yang, Yu Zhao, Bicheng Liu, Xiaoliang Zhang
Macrophage infiltration has been linked to the pathogenesis of diabetic nephropathy (DN). However, how infiltrating macrophages affect the progression of DN is unknown. Although infiltrating macrophages produce pro-inflammatory mediators and induce apoptosis in a variety of target cells, there are no studies in podocytes. Therefore, we tested the contribution of macrophages to podocytes apoptosis in DN. in vivo experiments showed that apoptosis in podocytes was increased in streptozocin (STZ)-induced diabetic rats compared with control rats and that this apoptosis was accompanied by increased macrophages infiltration in the kidney...
June 7, 2017: Oncotarget
https://www.readbyqxmd.com/read/28626027/selective-activation-of-epidermal-growth-factor-receptor-in-renal-proximal-tubule-induces-tubulointerstitial-fibrosis
#4
Jessica M Overstreet, Yinqiu Wang, Xin Wang, Aolei Niu, Leslie S Gewin, Bing Yao, Raymond C Harris, Ming-Zhi Zhang
Epidermal growth factor receptor (EGFR) has been implicated in the pathogenesis of diabetic nephropathy and renal fibrosis; however, the causative role of sustained EGFR activation is unclear. Here, we generated a novel kidney fibrotic mouse model of persistent EGFR activation by selectively expressing the EGFR ligand, human heparin-binding EGF-like growth factor (HB-EGF), in renal proximal tubule epithelium. Human HB-EGF expression increased tyrosine kinase phosphorylation of EGFR and the subsequent activation of downstream signaling pathways, including ERK and AKT, as well as the profibrotic TGF-β1/SMAD pathway...
June 16, 2017: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
https://www.readbyqxmd.com/read/28600173/autophagy-upregulation-ameliorates-cell-injury-in-sequestosome-1-knockout-podocytes-in-vitro
#5
Zhaoping Li, Yuan Yuan, Yan Meng, Ying Rong, Hao Bai, Liyong Chen
Autophagy is a catabolic process to maintain intracellular homeostasis that degrades damaged proteins and organelles in mammalian cells. Podocytes are crucial for maintaining the normal function of the glomerular filtration barrier. In the present study, we aimed to investigate the high glucose-induced cell injury in human podocytes and the protective role of autophagy in this process. Here we show that the autophagy activity was decreased under the high glucose conditions and 72 h of high glucose exposure inhibited the cell viablity and aggravated cell injury...
June 6, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28596971/soluble-urokinase-receptor-and-the-kidney-response-in-diabetes-mellitus
#6
REVIEW
Ranadheer R Dande, Vasil Peev, Mehmet M Altintas, Jochen Reiser
Diabetic nephropathy (DN) is the leading cause of end-stage renal disease (ESRD) worldwide. DN typically manifests by glomerular hyperfiltration and microalbuminuria; then, the disease progresses to impaired glomerular filtration rate, which leads to ESRD. Treatment options for DN include the strict control of blood glucose levels and pressure (e.g., intraglomerular hypertension). However, the search for novel therapeutic strategies is ongoing. These include seeking specific molecules that contribute to the development and progression of DN to potentially interfere with these "molecular targets" as well as with the cellular targets within the kidney such as podocytes, which play a major role in the pathogenesis of DN...
2017: Journal of Diabetes Research
https://www.readbyqxmd.com/read/28593583/regulating-autophagy-as-a-therapeutic-target-for-diabetic-nephropathy
#7
REVIEW
Munehiro Kitada, Yoshio Ogura, Itaru Monno, Daisuke Koya
PURPOSE OF REVIEW: Autophagy promotes cellular health in response to various cellular stresses and to changes in nutrient conditions. In this review, we focus on the role of autophagy in the pathogenesis of diabetic nephropathy and discuss the regulation of autophagy as a new therapeutic target for the suppression of diabetic nephropathy. RECENT FINDINGS: Previous studies have indicated that autophagy deficiency or insufficiency in renal cells, including podocytes, mesangial cells, endothelial cells and tubular cells, contributes to the pathogenesis of diabetic nephropathy...
July 2017: Current Diabetes Reports
https://www.readbyqxmd.com/read/28554965/fetuin-a-aggravates-lipotoxicity-in-podocytes-via-interleukin-1-signaling
#8
Jana M Orellana, Kapil Kampe, Friederike Schulze, Jonas Sieber, Andreas W Jehle
Sterile inflammation is considered critical in the pathogenesis of diabetic nephropathy (DN). Here we show that Fetuin-A (FetA) or lipopolysaccharide (LPS) exacerbate palmitic acid-induced podocyte death, which is associated with a strong induction of monocyte chemoattractant protein-1 (MCP-1) and keratinocyte chemoattractant (KC). Moreover, blockage of TLR4 prevents MCP-1 and KC secretion and attenuates podocyte death induced by palmitic acid alone or combined with FetA. In addition, inhibition of interleukin-1 (IL-1) signaling by anakinra, a recombinant human IL-1Ra, or a murinized anti-IL-1β antibody attenuates the inflammatory and ultimate cell death response elicited by FetA alone or combined with palmitic acid...
May 2017: Physiological Reports
https://www.readbyqxmd.com/read/28554737/podocyte-specific-jak2-overexpression-worsens-diabetic-kidney-disease-in-mice
#9
Hongyu Zhang, Viji Nair, Jharna Saha, Kevin B Atkins, Jeffrey B Hodgin, Thomas L Saunders, Martin G Myers, Thomas Werner, Matthias Kretzler, Frank C Brosius
Activation of JAK-STAT signaling has been implicated in the pathogenesis of diabetic kidney disease. An increased expression of JAK-STAT genes was found in kidney glomerular cells, including podocytes, in patients with early diabetic kidney disease. However, it is not known whether increased expression of JAK or STAT isoforms in glomerular cells can lead to worsening nephropathy in the setting of diabetes. Therefore, we overexpressed JAK2 mRNA specifically in glomerular podocytes of 129S6 mice to determine whether this change alone could worsen diabetic kidney disease...
May 26, 2017: Kidney International
https://www.readbyqxmd.com/read/28545434/effects-of-dangguibuxue-decoction-on-rat-glomerular-mesangial-cells-cultured-under-high-glucose-conditions
#10
Xiao-Dan Ren, Ying-Wen Zhang, Xiu-Ping Wang, Ya-Rong Li
BACKGROUND: Dysfunction of glomerular mesangial cells (GMCs) plays an important role in pathogenesis of diabetic nephropathy. Here, we investigated the effects of Dangguibuxue decoction (DBD), an herbal traditional Chinese medicinal (TCM) formula composed of Astragali Radix and Angelicae Sinensis Radix, on GMC proliferation and fibrogenesis under high-glucose (HG) conditions. METHODS: Sixty male Sprague Dawley rats were divided into 5 groups and administered intragastric 0...
May 25, 2017: BMC Complementary and Alternative Medicine
https://www.readbyqxmd.com/read/28540086/diabetic-nephropathy-time-to-withhold-development-and-progression-a-review
#11
REVIEW
Usama A A Sharaf El Din, Mona M Salem, Dina O Abdulazim
The recent discoveries in the fields of pathogenesis and management of diabetic nephropathy have revolutionized the knowledge about this disease. Little was added to the management of diabetic nephropathy after the introduction of renin angiotensin system blockers. The ineffective role of the renin- angiotensin system blockers in primary prevention of diabetic nephropathy in type 1 diabetes mellitus necessitated the search for other early therapeutic interventions that target alternative pathogenic mechanisms...
July 2017: Journal of Advanced Research
https://www.readbyqxmd.com/read/28539664/mirna-29c-regulates-the-expression-of-inflammatory-cytokines-in-diabetic-nephropathy-by-targeting-tristetraprolin
#12
Jia Guo, Jing Li, Jing Zhao, Shuguang Yang, Luyao Wang, Genyang Cheng, Dong Liu, Jing Xiao, Zhangsuo Liu, Zhanzheng Zhao
Diabetic nephropathy is one of the most prevalent chronic complications of Diabetes mellitus, but its pathogenesis remains elusive. This study was designed to determine the role of tristetraprolin (TTP), inflammatory cytokines and microRNAs (miRNAs) in DN. The blood and urine samples were obtained from 32 patients with DN, 33 patients with type 2 DM, and 35 normal healthy subjects as controls. Renal tissue samples were also obtained from 10 DN patients and 10 normal controls. The miRNA microarray analyses were performed in pooled plasma and urine sediment samples of eight DN patients and eight age- and sex-matched health control subjects and three paired renal tissues from patients with DN and normal controls...
May 24, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28497277/brazilin-ameliorates-diabetic-nephropathy-and-inflammation-in-db-db-mice
#13
Zhan-Yuan Li, Yu Zheng, Yan Chen, Min Pan, Shu-Bei Zheng, Wen Huang, Zhi-Hong Zhou, Han-Yang Ye
Hyperglycemia and inflammation play important roles in the pathogenesis of diabetic nephropathy (DN). Brazilin might be an effective pharmacological agent against hyperglycemia and inflammation. In our present study, we explored whether brazilin mitigated pathological progression, inflammation, and extracellular matrix (ECM) accumulation in a mouse model of diabetic nephropathy. Brazilin reduced aggravated biochemical indices of DN (proteinuria and the serum glucose level) and renal hypertrophy. Brazilin also improved renal morphology and inhibited macrophage infiltration, as manifested by different pathological staining methods...
May 11, 2017: Inflammation
https://www.readbyqxmd.com/read/28487945/nox4-is-involved-in-high-glucose-induced-apoptosis-in-renal-tubular-epithelial-cells-via-notch-pathway
#14
Min Yao, Feng Gao, Xiaomeng Wang, Yonghong Shi, Shuxia Liu, Huijun Duan
It has previously been demonstrated that nicotinamide adenine dinucleotide phosphate‑oxidase (NADPH) oxidase 4 (Nox4), is important in the pathogenesis of diabetic nephropathy (DN), however the exact mechanisms remain to be elucidated. The present study aimed to examine the effect of Nox4 on the alteration of the Notch pathway and cell apoptosis in the renal tubular epithelial cell line, HKC, under conditions of high glucose (HG; 30 mmol/l glucose). Nox4 and the Notch pathway were inhibited by N‑acetylcysteine (NAC), diphenylene iodonium (DPI) or γ‑secretase inhibitor (DAPT)...
June 2017: Molecular Medicine Reports
https://www.readbyqxmd.com/read/28486920/mitochondria-a-novel-therapeutic-target-in-diabetic-nephropathy
#15
Shikun Yang, Yachun Han, Jun Liu, Panai Song, Xiaoxuan Xu, Li Zhao, Chun Hu, Li Xiao, Fuyou Liu, Hao Zhang, Lin Sun
Diabetic nephropathy (DN) is an important diabetic microvascular complication, and it is becoming the leading cause of end-stage renal disease worldwide. Unfortunately, there are no effective therapies to treat established DN. Therefore, new therapeutic targets are urgently required. Accumulating studies indicate that mitochondrial dysfunction is central to the pathogenesis of DN, such as elevated oxidative stress induced by disorders of the mitochondrial respiratory chain complex and mitochondrial dynamic disorders...
May 9, 2017: Current Medicinal Chemistry
https://www.readbyqxmd.com/read/28453961/diabetic-nephropathy-new-insights-into-established-therapeutic-paradigms-and-novel-molecular-targets
#16
REVIEW
Dilip Sharma, Pallab Bhattacharya, Kiran Kalia, Vinod Tiwari
Diabetic nephropathy is one of the most prevalent microvascular complication in patients suffering from diabetes and is reported to be the major cause of renal failure when compared to any other kidney disease. Currently, available therapies provide only symptomatic relief and unable to treat the underlying pathophysiology of diabetic nephropathy. This review will explore new insights into the established therapeutic paradigms targeting oxidative stress, inflammation and endoplasmic reticulum stress with the focus on recent clinical developments...
June 2017: Diabetes Research and Clinical Practice
https://www.readbyqxmd.com/read/28428931/the-role-of-renal-proximal-tubule-transport-in-the-regulation-of-blood-pressure
#17
REVIEW
Shoko Horita, Motonobu Nakamura, Masashi Suzuki, Nobuhiko Satoh, Atsushi Suzuki, Yukio Homma, Masaomi Nangaku
The electrogenic sodium/bicarbonate cotransporter 1 (NBCe1) on the basolateral side of the renal proximal tubule plays a pivotal role in systemic acid-base homeostasis. Mutations in the gene encoding NBCe1 cause severe proximal renal tubular acidosis accompanied by other extrarenal symptoms. The proximal tubule reabsorbs most of the sodium filtered in the glomerulus, contributing to the regulation of plasma volume and blood pressure. NBCe1 and other sodium transporters in the proximal tubule are regulated by hormones, such as angiotensin II and insulin...
March 2017: Kidney Research and Clinical Practice
https://www.readbyqxmd.com/read/28401169/epigenetic-regulations-in-diabetic-nephropathy
#18
REVIEW
Zeyuan Lu, Na Liu, Feng Wang
Diabetic nephropathy (DN) is a chronic complication of diabetes and the most common cause of end-stage kidney disease. It has been reported that multiple factors are involved in the pathogenesis of DN, while the molecular mechanisms that lead to DN are still not fully understood. Numerous risk factors for the development of diabetic nephropathy have been proposed, including ethnicity and inherited genetic differences. Recently, with the development of high-throughput technologies, there is emerging evidence that suggests the important role of epigenetic mechanisms in the pathogenesis of DN...
2017: Journal of Diabetes Research
https://www.readbyqxmd.com/read/28393693/update-on-the-protective-renal-effects-of-metformin-in-diabetic-nephropathy
#19
Andreas Eisenreich, Ulrike Leppert
BACKGROUND: Diabetic nephropathy is one of the most important complications in patients with diabetes mellitus. Main steps crucial for the pathogenesis of diabetic nephropathy involve amongst others the modulation of cell signaling via AMP-activated kinase (AMPK) and mammalian target of rapamycin (mTOR), reactive oxygen generation, and endoplasmic reticulum stress under diabetic or hyperglycemic conditions. These processes mediate increased loss of renal cells, such as podocytes, which consequentially leads to renal damage and loss of renal functions, such as structural integrity and glomerular filtration in diabetic nephropathy...
April 4, 2017: Current Medicinal Chemistry
https://www.readbyqxmd.com/read/28387811/dual-therapy-targeting-the-endocannabinoid-system-prevents-experimental-diabetic-nephropathy
#20
Federica Barutta, Serena Grimaldi, Roberto Gambino, Kiran Vemuri, Alexandros Makriyannis, Laura Annaratone, Vincenzo di Marzo, Graziella Bruno, Gabriella Gruden
Background.: The endocannabinoid system has been implicated in the pathogenesis of diabetic nephropathy (DN). We investigated the effect of combined therapy with AM6545, a 'peripherally' restricted cannabinoid receptor type 1 (CB1R) neutral antagonist, and AM1241, a cannabinoid receptor type 2 (CB2R) agonist, in experimental DN. Methods.: Renal function and structure, podocyte proteins and markers of both fibrosis and inflammation were studied in streptozotocin-induced diabetic mice treated for 14 weeks with vehicle, AM6545, AM1241 and AM6545-AM1241...
April 6, 2017: Nephrology, Dialysis, Transplantation
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