Gene expression profiles of glomerular endothelial cells support their role in the glomerulopathy of diabetic mice (original) (raw)
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Long-term expression of glomerular genes in diabetic nephropathy
Nephrology Dialysis Transplantation, 2018
Background. Although diabetic nephropathy (DN) is the most common cause for end-stage renal disease in western societies, its pathogenesis still remains largely unclear. A different gene pattern of diabetic and healthy kidney cells is one of the probable explanations. Numerous signalling pathways have emerged as important pathophysiological mechanisms for diabetesinduced renal injury. Methods. Glomerular cells, as podocytes or mesangial cells, are predominantly involved in the development of diabetic renal lesions. While many gene assays concerning DN are performed with whole kidney or renal cortex tissue, we isolated glomeruli from black and tan, brachyuric (BTBR) obese/obese (ob/ob) and wildtype mice at four different timepoints (4, 8, 16 and 24 weeks) and performed an mRNA microarray to identify differentially expressed genes (DEGs). In contrast to many other diabetic mouse models, these homozygous ob/ob leptindeficient mice develop not only a severe type 2 diabetes, but also diabetic kidney injury with all the clinical and especially histologic features defining human DN. By functional enrichment analysis we were able to investigate biological processes and pathways enriched by the DEGs at different disease stages. Altered expression of nine randomly selected genes was confirmed by quantitative polymerase chain reaction from glomerular RNA. Results. Ob/ob type 2 diabetic mice showed up-and downregulation of genes primarily involved in metabolic processes and pathways, including glucose, lipid, fatty acid, retinol and amino acid metabolism. Members of the CYP4A and ApoB family were found among the top abundant genes. But more interestingly, altered gene loci showed enrichment for processes and pathways linked to angioneogenesis, complement cascades, semaphorin pathways, oxidation and reduction processes and renin secretion. Conclusion. The gene profile of BTBR ob/ob type 2 diabetic mice we conducted in this study can help to identify new key players in molecular pathogenesis of diabetic kidney injury.
Molecular Mechanisms in Early Diabetic Kidney Disease: Glomerular Endothelial Cell Dysfunction
International Journal of Molecular Sciences
Diabetic kidney disease (DKD) is the leading cause of end-stage renal disease (ESRD), with prevalence increasing at an alarming rate worldwide and today, there are no known cures. The pathogenesis of DKD is complex, influenced by genetics and the environment. However, the underlying molecular mechanisms that contribute to DKD risk in about one-third of diabetics are still poorly understood. The early stage of DKD is characterized by glomerular hyperfiltration, hypertrophy, podocyte injury and depletion. Recent evidence of glomerular endothelial cell injury at the early stage of DKD has been suggested to be critical in the pathological process and has highlighted the importance of glomerular intercellular crosstalk. A potential mechanism may include reactive oxygen species (ROS), which play a direct role in diabetes and its complications. In this review, we discuss different cellular sources of ROS in diabetes and a new emerging paradigm of endothelial cell dysfunction as a key event...
International Journal of Basic & Clinical Pharmacology, 2025
Diabetic nephropathy is the chronic loss of kidney function occurring due to diabetes mellitus. Due to increased sugar levels, there is disfunctioning of glomeruli, loss of protein in urine, and decrease in the levels of serum albumin that mainly leads to edema. The progression of renal disfunctioning starts when glomerular filtration rate is greater than 90ml/min. A large body of evidence indicates that oxidative stress is the main attributor involved in the progression of macro-vascular complications of diabetes. (ROS), NAD(P)H oxidase, advanced glycation end products (AGE), polyol pathway, uncoupled nitric oxide synthase (NOS), mitochondrial respiratory chain via oxidative phosphorylation, protein kinase C, mitogen-activated protein kinases, cytokines and transcription factors eventually cause increased expression of extracellular matrix (EC) genes with progression to fibrosis and end stage renal disease. Apart from these well-established pathways, major markers in the kidney disease which could work as potential targets has been explored like MCP-1, BMP-7, p38 MAPK, MiR-130b, HSP-27, AKT which further needs more research as they have shown promising results in their early level of studies. The present review aims to investigate the molecular targets involved in diabetic nephropathy, and to comprehend the intricate signalling pathways, such as JAK/STAT, BMP-7–Smad1/5/8 pathway, RhoA/ROCK, caspases, to which the aforementioned markers have either an independent or dependent relationship. If these signalling pathways are properly studied, these markers may aid in the treatment of the disease and its associated secondary effects such as nephropathy.
Transcriptomic Analysis in Diabetic Nephropathy of Streptozotocin-Induced Diabetic Rats
International Journal of Molecular Sciences, 2011
Diabetic nephropathy (DN) is a major complication of diabetes and is caused by an imbalance in the expression of certain genes that activate or inhibit vital cellular functions of kidney. Despite several recent advances, the pathogenesis of DN remains far from clear, suggesting the need to carry out studies identifying molecular aspects, such as gene expression, that could play a key role in the development of DN. There are several techniques to analyze transcriptome in living organisms. In this study, the suppression subtractive hybridization (SSH) method was used to generate up-and down-regulated subtracted cDNA libraries in the kidney of streptozotocin (STZ)-induced diabetic rats. Northern-blot analysis was used to confirm differential expression ratios from the obtained SSH clones to identify genes related to DN. 400 unique SSH clones were randomly chosen from the two subtraction libraries (200 of each) and verified as differentially expressed. According to blast screening and functional annotation, 20.2% and 20.9% of genes were OPEN ACCESS Int. J. Mol. Sci. 2011, 12 8432 related to metabolism proteins, 9% and 3.6% to transporters and channels, 16% and 6.3% to transcription factors, 19% and 17.2% to hypothetical proteins, and finally 24.1 and 17.2% to unknown genes, from the down-and up-regulated libraries, respectively. The down-and up-regulated cDNA libraries differentially expressed in the kidney of STZ diabetic rats have been successfully constructed and some identified genes could be highly important in DN.
Diabetes, 2006
Glomerular injury plays a pivotal role in the development of diabetic nephropathy. To elucidate molecular mechanisms underlying diabetic glomerulopathy, we compared glomerular gene expression profiles of db/db mice with those of db/m control mice at a normoalbuminuric stage characterized by hyperglycemia and at an early stage of diabetic nephropathy with elevated albuminuria, using cDNA microarray. In db/db mice at the normoalbuminuric stage, hypoxia-inducible factor-1α (HIF-1α), ephrin B2, glomerular epithelial protein 1, and Pod-1, which play key roles in glomerulogenesis, were already upregulated in parallel with an alteration of genes related to glucose metabolism, lipid metabolism, and oxidative stress. Podocyte structure-related genes, actinin 4α and dystroglycan 1 (DG1), were also significantly upregulated at an early stage. The alteration in the expression of these genes was confirmed by quantitative RT-PCR. Through pioglitazone treatment, gene expression of ephrin B2, Pod-1...
Diabetic Endothelial Nitric Oxide Synthase Knockout Mice Develop Advanced Diabetic Nephropathy
Journal of The American Society of Nephrology, 2007
The pathogenesis of diabetic nephropathy remains poorly defined, and animal models that represent the human disease have been lacking. It was demonstrated recently that the severe endothelial dysfunction that accompanies a diabetic state may cause an uncoupling of the vascular endothelial growth factor (VEGF)-endothelial nitric oxide (eNO) axis, resulting in increased levels of VEGF and excessive endothelial cell proliferation. It was hypothesized further that VEGF-NO uncoupling could be a major contributory mechanism that leads to diabetic vasculopathy. For testing of this hypothesis, diabetes was induced in eNO synthase knockout mice (eNOS KO) and C57BL6 controls. Diabetic eNOS KO mice developed hypertension, albuminuria, and renal insufficiency with arteriolar hyalinosis, mesangial matrix expansion, mesangiolysis with microaneurysms, and Kimmelstiel-Wilson nodules. Glomerular and peritubular capillaries were increased with endothelial proliferation and VEGF expression. Diabetic eNOS KO mice showed increased mortality at 5 mo. All of the functional and histologic changes were improved with insulin therapy. Inhibition of eNO predisposes mice to classic diabetic nephropathy. The mechanism likely is due to VEGF-NO uncoupling with excessive endothelial cell proliferation coupled with altered autoregulation consequent to the development of preglomerular arteriolar disease. Endothelial dysfunction in human diabetes is common, secondary to effects of glucose, advanced glycation end products, C-reactive protein, uric acid, and oxidants. It was postulated that endothelial dysfunction should predict nephropathy and that correction of the dysfunction may prevent these important complications.
Pathophysiology of Diabetic Nephropathy: Involvement of Multifaceted Signalling Mechanism
Journal of Cardiovascular Pharmacology, 2009
Diabetic nephropathy is a major cause of end-stage renal failure and the mortality rate due to this disease is continuously progressing worldwide. The multifaceted signalling mechanisms have been identified to be involved in the pathogenesis of diabetic nephropathy. Despite the modern therapies like antidiabetics, antihypertensives, and antioxidants available to treat diabetic nephropathy; most of patients continue to show progressive renal damage. It suggests that the key pathogenic mechanism involved in the induction and progression of diabetic nephropathy is still remaining active and unmodified by the present therapies. The purpose of this review is to bring together the current information concerning the signalling systems involved in the pathogenesis of diabetic nephropathy.
2018
Diabetic nephropathy (DN) is a major micro-vascular complication in diabetes mellitus (DM). One third of type 1 DM and 1/6 of type 2 DM develop DN account for more than 30% of total end stage renal disorders (ESRD), the main cause of renal replacement therapy. It is characterized by mesangial expansion, glomerulosclerosis and increased intracellular matrix accumulation. Injury of podocytes and reduced cellular density are considered to be root of the disease. Molecular mechanisms that leads diabetic patients toward nephropathy is hyperglycemia induced production of reactive oxygen species (ROS), advanced glycation end products (AGEs), activation of polyol pathway, increased expression of TGF-β, angiotensin II and aldosterone induced oxidative injury. DN can be prevented by controlling the glycemic levels, blood pressure, body weight and consumption of low protein diets along with high potassium supplementation. Therapeutic strategies including intensive glycemic control, blockage of...