scholarly journals High Elmo1 expression aggravates and low Elmo1 expression prevents diabetic nephropathy

2016 ◽  
Vol 113 (8) ◽  
pp. 2218-2222 ◽  
Author(s):  
Catherine K. Hathaway ◽  
Albert S. Chang ◽  
Ruriko Grant ◽  
Hyung-Suk Kim ◽  
Victoria J. Madden ◽  
...  
Keyword(s):  
Diabetic Nephropathy ◽  
Transforming Growth Factor ◽  
Association Studies ◽  
Lipid Peroxides ◽  
Transforming Growth Factor Β1 ◽  
Genome Wide Association Studies ◽  
Diabetic Mice ◽  
Stage Renal Disease ◽  
End Stage

Human genome-wide association studies have demonstrated that polymorphisms in the engulfment and cell motility protein 1 gene (ELMO1) are strongly associated with susceptibility to diabetic nephropathy. However, proof of causation is lacking. To test whether modest changes in its expression alter the severity of the renal phenotype in diabetic mice, we have generated mice that are type 1 diabetic because they have the Ins2Akita gene, and also have genetically graded expression of Elmo1 in all tissues ranging in five steps from ∼30% to ∼200% normal. We here show that the Elmo1 hypermorphs have albuminuria, glomerulosclerosis, and changes in the ultrastructure of the glomerular basement membrane that increase in severity in parallel with the expression of Elmo 1. Progressive changes in renal mRNA expression of transforming growth factor β1 (TGFβ1), endothelin-1, and NAD(P)H oxidase 4 also occur in parallel with Elmo1, as do the plasma levels of cystatin C, lipid peroxides, and TGFβ1, and erythrocyte levels of reduced glutathione. In contrast, Akita type 1 diabetic mice with below-normal Elmo1 expression have reduced expression of these various factors and less severe diabetic complications. Remarkably, the reduced Elmo1 expression in the 30% hypomorphs almost abolishes the pathological features of diabetic nephropathy, although it does not affect the hyperglycemia caused by the Akita mutation. Thus, ELMO1 plays an important role in the development of type 1 diabetic nephropathy, and its inhibition could be a promising option for slowing or preventing progression of the condition to end-stage renal disease.

scholarly journals Immunomodulatory Effects of the Nutraceutical Garlic Derivative Allicin in the Progression of Diabetic Nephropathy

2018 ◽  
Vol 19 (10) ◽  
pp. 3107 ◽  
Author(s):  
Abraham Arellano Buendía ◽  
Montserrat Tostado González ◽  
Omegar Sánchez Reyes ◽  
Fernando García Arroyo ◽  
Raúl Argüello García ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Diabetic Nephropathy ◽  
Proinflammatory Cytokines ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β1 ◽  
The Status ◽  
Nuclear Factor Kappa Beta ◽  
Stage Renal Disease ◽  
End Stage

Diabetic nephropathy (DN) is presently the primary cause of chronic kidney disease and end-stage renal disease (ESRD). It has been suggested that inflammation and oxidative stress, in addition to or in concert with the metabolic changes, plays an important role in the maintenance and progression of the disease. Therefore, attenuating or blocking these mechanisms may be a therapeutic target to delay the progression of the disease. Diallyl thiosulfinate (allicin), a compound derived from garlic, inhibits free radical formation, increases glutathione synthesis and decreases the levels of proinflammatory molecules in vitro. This research aimed to assess the effect of allicin on oxidative stress and inflammation-induced diabetes. Animals were divided into control and diabetes (streptozotocin 50 mg/kg i.p.), and maintained for 30 days. After 30 days, the group of diabetic animals was subdivided into diabetes and allicin-treated diabetes (16 mg/kg/day oral gavage). The three experimental groups were maintained for another month. We analyzed the status of renal function, oxidative stress and proinflammatory cytokines. The untreated diabetic group showed hyperglycemia and increased diuresis, creatinine clearance, proteinuria, glycosuria and urinary excretion of N-acetyl-β-d-glucosaminidase (NAG), as well as increased oxidative stress and the expression of interleukin 1β (IL-1β), IL-6, nuclear factor kappa beta (NFκβ) and transforming growth factor-β1 (TGF-β1) in plasma and kidney. In contrast, the inhibitor of NFκβ (Iκβ) is decreased in the cortex. It has been demonstrated that the allicin treatment decreases hyperglycemia, polyuria, and NAG excretion. The oxidative stress and proinflammatory cytokines were also reduced by the allicin treatment. In conclusion, allicin delays the progression of diabetic nephropathy through antioxidant and anti-inflammatory mechanisms.

scholarly journals Transforming growth factor-β1 hyperexpression in African American end-stage renal disease patients

1998 ◽  
Vol 53 (3) ◽  
pp. 639-644 ◽  
Author(s):  
Manikkam Suthanthiran ◽  
Ashwani Khanna ◽  
David Cukran ◽  
Rohini Adhikarla ◽  
Vijay K. Sharma ◽  
...  
Keyword(s):  
African American ◽  
Growth Factor ◽  
Renal Disease ◽  
End Stage Renal Disease ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β1 ◽  
Stage Renal Disease ◽  
End Stage

scholarly journals Urinary Adiponectin Is an Independent Predictor of Progression to End-Stage Renal Disease in Patients With Type 1 Diabetes and Diabetic Nephropathy

Diabetes Care ◽  
2015 ◽  
Vol 38 (5) ◽  
pp. 883-890 ◽  
Author(s):  
Nicolae M. Panduru ◽  
Markku Saraheimo ◽  
Carol Forsblom ◽  
Lena M. Thorn ◽  
Daniel Gordin ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Diabetic Nephropathy ◽  
Renal Disease ◽  
End Stage Renal Disease ◽  
Independent Predictor ◽  
Stage Renal Disease ◽  
End Stage

scholarly journals Autophagy in diabetic nephropathy

2014 ◽  
Vol 224 (1) ◽  
pp. R15-R30 ◽  
Author(s):  
Yan Ding ◽  
Mary E Choi
Keyword(s):  
Type 2 Diabetes ◽  
Diabetic Nephropathy ◽  
Transforming Growth Factor ◽  
Renin Angiotensin System ◽  
Human Kidney ◽  
Nutrient Sensing ◽  
Signal Pathways ◽  
End Stage

Diabetic nephropathy (DN) is the most common cause of end-stage kidney disease worldwide, and is associated with increased morbidity and mortality in patients with both type 1 and type 2 diabetes. Increasing prevalence of diabetes has made the need for effective treatment of DN critical and thereby identifying new therapeutic targets to improve clinical management. Autophagy is a highly conserved ‘self-eating’ pathway by which cells degrade and recycle macromolecules and organelles. Autophagy serves as an essential mechanism to maintain homeostasis of glomeruli and tubules, and plays important roles in human health and diseases. Impairment of autophagy is implicated in the pathogenesis of DN. Emerging body of evidence suggests that targeting the autophagic pathway to activate and restore autophagy activity may be renoprotective. In this review, we examine current advances in our understanding of the roles of autophagy in diabetic kidney injury, focusing on studies in renal cells in culture, human kidney tissues, and experimental animal models of diabetes. We discuss the major nutrient-sensing signal pathways and diabetes-induced altered intracellular metabolism and cellular events, including accumulation of advanced glycation end-products, increased oxidative stress, endoplasmic reticulum stress, hypoxia, and activation of the renin–angiotensin system, which modulate autophagic activity and contribute to the development of DN. We also highlight recent studies of autophagy and transforming growth factor-β in renal fibrosis, the final common response to injury that ultimately leads to end-stage kidney failure in both type 1 and type 2 diabetes. These findings suggest the possibility that autophagy can be a therapeutic target against DN.

scholarly journals The Role of Tyrosine Kinase Receptors in Peritoneal Fibrosis

2015 ◽  
Vol 35 (5) ◽  
pp. 497-505 ◽  
Author(s):  
Li Wang ◽  
Shougang Zhuang
Keyword(s):  
Tyrosine Kinases ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β1 ◽  
Peritoneal Fibrosis ◽  
Functional Changes ◽  
Ultrafiltration Failure ◽  
Stage Renal Disease ◽  
End Stage

Peritoneal dialysis (PD) is a modality for treatment of patients with end-stage renal disease (ESRD) that depends on the structural and functional integrity of the peritoneal membrane. However, long-term PD can lead to morphological and functional changes in the peritoneum; in particular, peritoneal fibrosis has become one of the most common complications that ultimately results in ultrafiltration failure (UFF) and discontinuation of PD. Several factors and mechanisms such as inflammation and overproduction of transforming growth factor-β1 have been implicated in the development of peritoneal fibrosis, but there is no effective therapy to prevent or delay this process. Recent studies have shown that activation of multiple receptor tyrosine kinases (RTKs) is associated with the development and progression of tissue fibrosis in various organs, and there are also reports indicating the involvement of some RTKs in peritoneal fibrosis. This review will describe the role and mechanisms of RTKs in peritoneal fibrosis and discuss the possibility of using them as therapeutic targets for prevention and treatment of this complication.

scholarly journals PNPLA3 gene and kidney disease

2020 ◽  
Vol 1 (1) ◽  
pp. 42-50 ◽  
Author(s):  
Alessandro Mantovani ◽  
Chiara Zusi
Keyword(s):  
Kidney Disease ◽  
Association Studies ◽  
Liver Steatosis ◽  
Kidney Injury ◽  
Future Perspective ◽  
Genome Wide Association Studies ◽  
Alcoholic Fatty Liver ◽  
Liver And Kidney ◽  
Stage Renal Disease ◽  
End Stage

Chronic kidney disease (CKD) is a disease regularly seen in clinical practice. At present, CKD is described as a change of kidney structure and/or function and it is classified in relation to cause, values of glomerular filtration rate and albuminuria category. Seeing that CKD is closely linked to the development of end-stage renal disease and other comorbidities, the determination of additional independent predictors for CKD is clinically necessary. At present, there is evidence associating non-alcoholic fatty liver disease (NAFLD) with CKD, thereby suggesting that NAFLD patients may require intensive surveillance to reduce their risk of CKD. In 2008, genome-wide association studies documented an association between the variant rs738409 (C > G p.I148M) in the patatin-like phospholipase domain containing 3 (PNPLA3) gene (mainly implicated in the lipid regulation) and the entire spectrum of NAFLD (i.e., liver steatosis, non-alcoholic steatohepatitis, fibrosis, and hepatocellular carcinoma). In the last years, accumulating epidemiological evidence suggests the existence of a relationship between PNPLA3 rs738409 and risk of CKD, indicating that rs738409 may also contribute to the kidney injury. This is of particular scientific interest, as such association may explain, at least in part, the epidemiological association between liver and kidney disease. In this narrative review, we will discuss the accumulating evidence regarding the association between PNPLA3 rs738409 and risk of CKD, the putative biological mechanisms underpinning such relationship, and the possible future perspective.

scholarly journals Epigenetics of Diabetic Nephropathy: From Biology to Therapeutics

2020 ◽  
pp. 48-57
Author(s):  
Keith Al-Hasani ◽  
Ishant Khurana ◽  
Theresa Farhat ◽  
Assaad Eid ◽  
Assam El-Osta
Keyword(s):  
Diabetic Nephropathy ◽  
End Stage Renal Disease ◽  
Kidney Development ◽  
Kidney Cells ◽  
Epigenetic Mechanisms ◽  
Stage Renal Disease ◽  
End Stage ◽  
Diseased Kidney

Diabetic nephropathy (DN) is a lethal microvascular complication associated with Type 1 and Type 2 diabetes mellitus, and is the leading single cause of end-stage renal disease. Although genetic influences are important, epigenetic mechanisms have been implicated in several aspects of the disease. The current therapeutic methods to treat DN are limited to slowing disease progression without repair and regeneration of the damaged nephrons. Replacing dying or diseased kidney cells with new nephrons is an attractive strategy. This review considers the genetic and epigenetic control of nephrogenesis, together with the epigenetic mechanisms that accompany kidney development and recent advances in induced reprogramming and kidney cell regeneration in the context of DN.

scholarly journals Role of Endothelial Nitric Oxide Synthase in Diabetic Nephropathy: Lessons from Diabetic eNOS Knockout Mice

2014 ◽  
Vol 2014 ◽  
pp. 1-17 ◽  
Author(s):  
Takamune Takahashi ◽  
Raymond C. Harris
Keyword(s):  
Animal Model ◽  
Diabetic Nephropathy ◽  
Critical Role ◽  
Therapeutic Interventions ◽  
Diabetic Mice ◽  
Model Study ◽  
Animal Model Study ◽  
Stage Renal Disease ◽  
End Stage

Diabetic nephropathy (DN) is the leading cause of end-stage renal disease in many countries. The animal models that recapitulate human DN undoubtedly facilitate our understanding of this disease and promote the development of new diagnostic markers and therapeutic interventions. Based on the clinical evidence showing the association of eNOS dysfunction with advanced DN, we and others have created diabetic mice that lack eNOS expression and shown that eNOS-deficient diabetic mice exhibit advanced nephropathic changes with distinct features of progressive DN, including pronounced albuminuria, nodular glomerulosclerosis, mesangiolysis, and arteriolar hyalinosis. These studies clearly defined a critical role of eNOS in DN and developed a robust animal model of this disease, which enables us to study the pathogenic mechanisms of progressive DN. Further, recent studies with this animal model have explored the novel mechanisms by which eNOS deficiency causes advanced DN and provided many new insights into the pathogenesis of DN. Therefore, here we summarize the findings obtained with this animal model and discuss the roles of eNOS in DN, unresolved issues, and future investigations of this animal model study.

scholarly journals Development of Biomarkers and Molecular Therapy Based on Inflammatory Genes in Diabetic Nephropathy

2021 ◽  
Vol 22 (18) ◽  
pp. 9985
Author(s):  
Amit K. Maiti
Keyword(s):  
Diabetic Nephropathy ◽  
Molecular Therapy ◽  
Renal Physiology ◽  
Complex Nature ◽  
Diabetic Patients ◽  
Renal Tubules ◽  
Stage Renal Disease ◽  
End Stage ◽  
Inflammatory Molecules

Diabetic Nephropathy (DN) is a debilitating consequence of both Type 1 and Type 2 diabetes affecting the kidney and renal tubules leading to End Stage Renal Disease (ESRD). As diabetes is a world epidemic and almost half of diabetic patients develop DN in their lifetime, a large group of people is affected. Due to the complex nature of the disease, current diagnosis and treatment are not adequate to halt disease progression or provide an effective cure. DN is now considered a manifestation of inflammation where inflammatory molecules regulate most of the renal physiology. Recent advances in genetics and genomic technology have identified numerous susceptibility genes that are associated with DN, many of which have inflammatory functions. Based on their role in DN, we will discuss the current aspects of developing biomarkers and molecular therapy for advancing precision medicine.

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