diabetic nephropathy
211097777
Puerarin Attenuates Diabetic Nephropathy by Promoting Autophagy in Podocytes
Puerarin, an active compound of radix puerariae, is a major compound used in Chinese herbal medicines to treat patients with diabetic nephropathy (DN) In the previous studies, we showed that puerarin exerts renoprotective effects in Streptozocin (STZ) induced diabetic mice through activation of Sirt1 and anti oxidative effects. Here, we further investigated the underlying mechanism mediating the renal protective effects of puerarin in DN. We studied the effects and mechanism of puerarin in STZ induced diabetic mice and in cultured immortalized mouse podocytes treated with high glucose. We confirmed that puerarin ameliorated urinary albumin creatinine ratio and kidney injury in STZ induced DN mice. We found that expression of heme oxygenase 1 (HMOX 1) and Sirt1 was suppressed in diabetic glomeruli but restored by puerarin treatment at both mRNA and protein levels. Additionally, we found that puerarin induced autophagy in the kidney of DN mice. In conditionally immortalized mouse podocytes, puerarin inhibited HG induced apoptosis and restored the mRNA and protein levels of HMOX 1 and Sirt1. Interestingly, we showed that puerarin decreased liver kinase B1 (LKB1) acetylation, thereby promoting adenosine 5' monophosphate activated protein kinase dependent autophagy. Knockdown of HMOX 1 and Sirt1 expression or treatment with the autophagy inhibitor 3 methyladenine abolished the protective effects of puerarin in HG treated podocytes. Taken together, these results suggest that puerarin protects podocytes from diabetes induced injury through HMOX1 and Sirt1 mediated upregulation of autophagy, a novel mechanism explaining its renal protective effects in DN.
Frontiers in Physiology
Xueling Li Qingqing Zhu Rong Zheng Jiayi Yan Minggang Wei Yichen Fan Yueyi Deng Yifei Zhong
182135851
The Single Cell Transcriptomic Landscape of Early Human Diabetic Nephropathy
Diabetic nephropathy is characterized by damage to both the glomerulus and tubulointerstitium, but relatively little is known about accompanying cell specific changes in gene expression. We performed unbiased single nucleus RNA sequencing (snRNAseq) on cryopreserved human diabetic kidney samples to generate 23,980 single nucleus transcriptomes from three control and three early diabetic nephropathy samples. All major cell types of the kidney were represented in the final dataset. Side by side comparison demonstrated cell type specific changes in gene expression that are important for ion transport, angiogenesis, and immune cell activation. In particular, we show that the diabetic loop of Henle, late distal convoluted tubule, and principal cells all adopt a gene expression signature consistent with increased potassium secretion, including alterations in Na K+ ATPase, WNK1, mineralocorticoid receptor and NEDD4L expression, as well as decreased paracellular calcium and magnesium reabsorption. We also identify strong angiogenic signatures in glomerular cell types, proximal convoluted tubule, distal convoluted tubule and principal cells. Taken together, these results suggest that increased potassium secretion and angiogenic signaling represent early kidney responses in human diabetic nephropathy. Significance Statement Single nucleus RNA sequencing revealed gene expression changes in early diabetic nephropathy that promote urinary potassium secretion and decreased calcium and magnesium reabsorption. Multiple cell types exhibited angiogenic signatures, which may represent early signs of aberrant angiogenesis. These alterations may help to identify biomarkers for disease progression or signaling pathways amenable to early intervention.
Parker C Wilson Haojia Wu Yuhei Kirita Kohei Uchimura Helmut G Rennke Paul A Welling Sushrut S Waikar Benjamin D Humphreys
59223903
Diabetic nephropathy: recent advances in pathophysiology and challenges in dietary management
BackgroundDiabetic nephropathy (DN) or diabetic kidney disease refers to the deterioration of kidney function seen in chronic type 1 and type 2 diabetes mellitus patients. The progression of the disease is known to occur in a series of stages and is linked to glycemic and blood pressure control. However, despite aggressive blood sugar control the prevalence of chronic kidney disease (CKD) in diabetic patients has not witnessed any decrease in the last two decades; which has lead to identification of additional factors in its progression. The nutritional status of patients is an important and modifiable factor that may influence CKD processes and outcome. It directly stems from the traditional dietary choices that patients make due to poor nutritional awareness. Dietary management of DN patients is challenging, as the twin factors of diet overload on kidney function needs to be balanced with malnutrition. Patient education seems to be the key in avoiding overindulgence of carbohydrate and protein rich foods while favoring inclusion of essential fats in their diet.ConclusionThis review will summarize current advances in staging and molecular pathogenesis of DN. It will highlight recent studies focusing on patient customized dietary interventions that offer new hope as an effective tool in improving quality of life and delaying disease progression in DN patients.
Diabetology Metabolic Syndrome
Mahaboob K Sulaiman
211537469
Metformin Reduces the Senescence of Renal Tubular Epithelial Cells in Diabetic Nephropathy via the MBNL1/miR 130a 3p/STAT3 Pathway
Senescence of renal tubular epithelial cells plays an important role in diabetic nephropathy, but the mechanism is unknown. Metformin may alleviate diabetic nephropathy by reducing this senescence. This study is aimed at clarifying the effects and mechanism of metformin on the senescence of renal tubular epithelial cells in diabetic nephropathy. We found that metformin reduced the expression of senescence associated gene P21 in high glucose induced (30 mmol/L) renal tubular epithelial cells and decreased the b galactosidase positive staining rate (decreased 16% p 0.01) Metformin was able to reduce senescence by upregulating the expression of RNA binding protein MBNL1 and miR 130a 3p and reducing STAT3 expression. MBNL1 prolonged the half life of miR 130a 3p, and miR 130a 3p could negatively regulate STAT3 by binding to its mRNA 3'UTR. In db/db diabetic mice, we found an enhanced senescence level combined with low expression of MBNL1 and miR 130a 3p and high expression of STAT3 compared with db/m control mice during nephropathy development. Meanwhile, metformin (200 mg/kg/day) could increase the expression of MBNL1 and miR 130a 3p and decreased STAT3 expression, thus reducing this senescence in db/db mice. Our results suggest that metformin reduces the senescence of renal tubular epithelial cells in diabetic nephropathy via the MBNL1/miR 130a 3p/STAT3 pathway, which provided new ideas for the therapy of this disease.
Oxidative medicine and cellular longevity
Xue Jiang Xuelei Ruan Yi Xue Shuang Yang Mai Shi Li-Ning Wang
58577757
Diabetic nephropathy: An update on pathogenesis and drug development.
Diabetic nephropathy (DN) is a major cause of end stage renal disease and affects a large number of individuals with diabetes. However, the development of specific treatments for DN has not yet been identified. Hence, this review is concisely designed to understand the molecular pathways leading to DN in order to develop suitable therapeutic strategies. Extensive literature search have been carried in regard with the pathogenesis and pathophysiology of DN, drug targets and updates on clinical trials, the consequences associated with DN and the potential biomarkers for diagnosis and prediction of DN are discussed in this review. DN is characterised by microalbuminuria and macroalbuminuria, and morphological changes such as glomerular thickening, interstitial fibrosis, formation of nodular glomerulosclerosis and decreased endothelial cell fenestration. Besides, the involvement of renin angiotensin aldosterone system, inflammation and genetic factors are the key pathways in the progression of DN. In regard with drug development drugs targeted to epidermal growth factor, inflammatory cytokines, ACTH receptor and TGFb1 receptors are in pipeline for clinical trials whereas, several drugs have also failed in phase III and phase IV of clinical trials due to lack of efficacy and severe adverse effect. The research on DN is limited with respect to its pathogenesis and drug development. Thus, a more detailed understanding of the pathogenesis of DN is very essential to progress in the drug development process.
Diabetes metabolic syndrome
Vikram Rao A/L B Vasanth Rao Sean Hong Tan Mayuren Candasamy Subrat Kumar Bhattamisra
221368424
FABP1 and FABP2 as markers of diabetic nephropathy
Background: Diabetes mellitus is the leading cause of diabetic nephropathy and a major public health issue worldwide. Approximately 20 30% of patients with type 2 diabetes mellitus (T2DM) have renal impairment. Fatty acid binding protein 1 (FABP1) is expressed in renal proximal tubule cells and released into urine in response to hypoxia caused by decreased peritubular capillary blood flow, and FABP2 is responsible for the transport of free fatty acids in the intestinal endothelium cells. There is increasing evidence that FABP1 and FABP 2 play a role in the development and progression of chronic kidney disease. The aim of this study was to investigate the relation of circulating FABP1 and FABP2 levels to nephropathy in patients with T2DM. Methods: For this study, 268 subjects with T2DM who were enrolled in a disease management program were stratified according to urinary microalbumin and serum creatinine measurements. The plasma FABP1 and FABP2 concentrations were examined by enzyme linked immunosorbent assay. Demographic and potential metabolic confounding factors were analyzed with logistic regression to calculate the effects of FABP1 and FABP2 levels on diabetic nephropathy. Results: The FABP1 and FABP2 levels increased in parallel with the advancement of diabetic nephropathy. Increasing concentrations of FABP1 and FABP2 were independently and significantly associated with diabetic nephropathy. Multiple logistic regression analysis revealed FABP1 and FABP2 as an independent association factor for diabetic nephropathy, even after full adjustment of known biomarkers. Furthermore, receiver operating characteristic curve analysis showed that a FABP1 level of >33.8 ng/mL and a FABP2 level of >2.8 ng/mL were associated with diabetic nephropathy. Conclusion: Our results suggest that FABP1 and FABP2 may be novel biomarkers of diabetic nephropathy.
International journal of medical sciences
I-Ting Tsai Cheng-Ching Wu Wei Chin Hung Thung-Lip Lee Chin-Feng Hsuan Ching-Ting Wei Yung-Chuan Lu Teng-Hung Yu Fu-Mei Chung Yau-Jiunn Lee Chao-Ping Wang
77395143
Stem cell derived extracellular vesicles inhibit and revert fibrosis progression in a mouse model of diabetic nephropathy
Extracellular vesicles (EVs) that are derived from mesenchymal stromal cells (MSCs) have been shown to reprogram injured cells by activating regenerative processes. We herein investigate the potential therapeutic effect of EVs, shed by human bone marrow MSCs and by human liver stem like cells (HLSCs) on the progression and reversion of fibrosis in a mouse model of diabetic nephropathy, as induced by streptozotocin. After the development of nephropathy, stem cell derived EVs were administered weekly to diabetic mice for four weeks. The stem cell derived EV treatment, but not the fibroblast EV treatment that was used as a control, significantly ameliorated functional parameters, such as albumin/creatinine excretion, plasma creatinine and blood urea nitrogen, which are altered in diabetic mice. Moreover, the renal fibrosis that develops during diabetic nephropathy progression was significantly inhibited in stem cell EV treated animals. A correlation was found between the down regulation of several pro fibrotic genes in renal tissues and the anti fibrotic effect of HLSC and MSC EVs. A comparative analysis of HLSC and MSC EV miRNA content highlighted some common and some specific patterns of miRNAs that target predicted pro fibrotic genes. In conclusion, stem cell derived EVs inhibit fibrosis and prevent its progression in a model of diabetes induced chronic kidney injury.
Scientific Reports
Cristina Grange Stefania Tritta Marta Tapparo Massimo Cedrino Ciro Tetta Giovanni Camussi Maria Felice Brizzi
51726109
Circular RNA circRNA_15698 aggravates the extracellular matrix of diabetic nephropathy mesangial cells via miR 185/TGF b1
Circular RNAs (circRNAs) are a novel type of noncoding RNAs that modulate the pathogenesis of multiple diseases. Nevertheless, the role of circRNAs in diabetic nephropathy (DN) pathogenesis is still ambiguous. In the current study, our team aims to investigate the expression profiles of circRNAs in DN and identify the function of circRNA on mesangial cells. CircRNAs microarray analysis revealed dysregulated circRNA in db/db DN mice, and circRNA_15698 was validated to be upregulated in both db/db mice and mouse mesangial cells (SV40 MES13) that were exposed to high glucose (25 mM) using real time polymerase chain reaction. Loss of functional experiments showed that circRNA_15698 knockdown significantly inhibited the expression levels of collagen type I (Col. I) collagen type IV (Col. IV) and fibronectin. Moreover, the cellular localization of circRNA_15698 was mainly in the cytoplasm. Bioinformatics tools and luciferase reporter assay confirmed that circRNA_15698 acted as a 'sponge' of miR 185, and then positively regulated the transforming growth factor b1 (TGF b1) protein expression, suggesting a circRNA_15698/miR 185/TGF b1 pathway. Further validation experiments validated that circRNA_15698/miR 185/TGF b1 promoted extracellular matrix (ECM) related protein synthesis. In summary, our study preliminarily investigates the role of circRNAs in mesangial cells and ECM accumulation, providing a novel insight for DN pathogenesis.
Journal of cellular physiology
Wei Hu Qing Han Lei Zhao Li Wang
59528025
Role of sirtuin 1 in diabetic nephropathy
Diabetic nephropathy (DN) is a research priority for scientists around the world because of its high prevalence and poor prognosis. Although several mechanisms have been shown to be involved in its pathogenesis and many useful drugs have been developed, the management of DN remains challenging. Increasing amounts of evidence show that silent information regulator 2 homolog 1 (sirtuin 1) a nicotinamide adenine dinucleotide (NAD+ dependent protein deacetylase, plays a crucial role in the pathogenesis and development of DN. Clinical data show that gene polymorphisms of sirtuin 1 affect patient vulnerability to DN. In addition, upregulation of sirtuin 1 attenuates DN in various experimental models of diabetes and in renal cells, including podocytes, mesangial cells, and renal proximal tubular cells, incubated with high concentrations of glucose or advanced glycation end products. Mechanistically, sirtuin 1 has its renoprotective effects by modulating metabolic homeostasis and autophagy, resisting apoptosis and oxidative stress, and inhibiting inflammation through deacetylation of histones and the transcription factors p53, forkhead box group O, nuclear factor kB, hypoxia inducible factor 1a, and others. Furthermore, some microRNAs have been implicated in the progression of DN because they target sirtuin 1 mRNA. Several synthetic drugs and natural compounds have been identified that upregulate the expression and activity of sirtuin 1, which protects against DN. The present review will summarize advances in knowledge regarding the role of sirtuin 1 in the pathogenesis of DN. The available evidence implies that sirtuin 1 has great potential as a clinical target for the prevention and treatment of diabetes.
Journal of Molecular Medicine
Wan-ning Wang Weixia Sun Yanli Cheng Zhonggao Xu Lu Cai
78091322
Exosome secreted from adipose derived stem cells attenuates diabetic nephropathy by promoting autophagy flux and inhibiting apoptosis in podocyte
BackgroundIt is confirmed that adipose derived stem cells (ADSCs) transplantation effectively relieves kidney fibrosis and type 2 diabetes disease in mice. Currently, exosome from urine derived stem cells (USCs) can protect type 1 diabetes mediated kidney injury and attenuate podocyte damage in diabetic nephropathy (DN) Exosome derived from USCs has evolved into the strategy for DN treatment, but the role of ADSCs derived exosome (ADSCs Exo) in DN remains unclear. The present study is aimed to investigate the therapeutic action and molecular mechanism of ADSCs derived exosome on DN.MethodsADSCs and exosome were authenticated by immunofluorescence and flow cytometry. Morphology and the number of exosome were evaluated by electron microscope and Nanosight Tracking Analysis (NTA) respectively. Cell apoptosis was assessed using flow cytometry. Podocyte autophagy and signaling transduction were measured by immunofluorescence and immunoblotting. Dual Luciferase Reporter assay was employed to detect the regulatory relationship between miR 486 and Smad1.ResultsADSCs Exo attenuated spontaneous diabetes by reducing levels of urine protein, serum creatinine (Scr) blood urea nitrogen (BUN) and podocyte apoptosis in mice. In in vitro experiment, ADSCs Exo also reversed high glucose induced decrease of cell viability and the increase of cell apoptosis in MPC5 cells. In terms of mechanism, ADSCs Exo could enhance autophagy flux and reduce podocyte injury by inhibiting the activation of mTOR signaling in MPC5 and spontaneous diabetic mice. Eventually, we found that miR 486 was the key factors in ADSCs and in the process of ADSCs Exo mediated improvement of DN symptom in vivo and in vitro. miR 486 reduced Smad1 expression by target regulating Smad1 whose reduction could inhibit mTOR activation, leading to the increase of autophagy and the reduction of podocyte apoptosis.ConclusionsIn conclusion, we illustrated that ADSCs Exo vividly ameliorated DN symptom by enhancing the expression of miR 486 which led to the inhibition of Smad1/mTOR signaling pathway in podocyte. Possibly, ADSCs Exo was used as a main therapeutic strategy for DN in future.
Stem Cell Research Therapy
Juan Jin Yi-fen Shi Jianguang Gong Li Zhao Yiwen Li Qiang He He Huang