Deletion of platelet-derived growth factor receptor-β improves diabetic nephropathy in Ca2+/calmodulin-dependent protein kinase IIα (Thr286Asp) transgenic mice (original) (raw)
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Over‐expression of platelet‐derived growth factor in human diabetic nephropathy
Nephrology Dialysis Transplantation, 2003
The pathogenetic mechanisms responsible for progressive renal impairment of diabetic nephropathy are still poorly understood, despite its growing incidence. Increasing evidence suggests that growth factors may contribute to the initiation and progressive fibrosis of diabetic nephropathy. In this study, the gene expression and protein distribution of platelet-derived growth factor-A and -B (PDGF-A and PDGF-B) in human diabetic nephropathy were examined. PDGF-A and PDGF-B mRNA levels in surplus renal biopsy tissue from seven patients with overt diabetic nephropathy and six nephrectomy samples were examined using quantitative reverse transcription-polymerase chain reaction (RT-PCR). In addition, each sample was also examined immunohistochemically to quantify and localize peptide expression of each PDGF isoform. Gene expression of PDGF-A and PDGF-B mRNA were increased 22- and 6-fold, respectively, in biopsies from patients with diabetic nephropathy compared with control tissue. Immunostaining also demonstrated increased peptide expression of both PDGF-A and PDGF-B in diabetic nephropathy, with each isoform showing a specific pattern of tissue distribution. The findings of increased gene and protein expression of PDGF in renal biopsies from patients with diabetic nephropathy imply a potential role for this prosclerotic growth factor in the development of the progressive fibrosis that characterizes human diabetic kidney disease.
The FASEB Journal, 2007
Diabetic nephropathy (DN) remains a major complication in both type 1 and type 2 diabetes. Systemic administration of antitransforming growth factor- (TGF-) antibody has shown some promise in mouse models of DN. However, chronic blockade of the multifunctional TGB- could be problematic. Several downstream effects of TGF- are mediated by connective tissue growth factor (CTGF), which is upregulated in several renal cells and secreted in the urine in the diabetic state. Using murine models of DN (type 1 and type 2) and a CTGF antisense oligonucleotide (ASO) of novel chimeric chemistry, we evaluated the specific role of this target in DN. In the type 1 model of DN, C57BL6 mice were made diabetic using streptozotocin injections and hyperglycemic animals were treated with CTGF ASOs (20 mg/kg/2 qw) for 4 months. ASO, but not mismatch control oligonucleotide, -treated animals showed significant reduction in target CTGF expression in the kidney with a concomitant decrease in proteinuria and albuminuria. Treatment with the CTGF ASO for 8 wk reduced serum creatinine and attenuated urinary albuminuria and proteinuria in diabetic db/db mice, a model of type 2 DN. The ASO also reduced expression of genes involved in matrix expansion such as fibronectin and collagen (I and IV) and an inhibitor of matrix degradation, PAI-1, in the renal cortex, contributing to significant reversal of mesangial expansion in both models of DN. Pathway analyses demonstrated that diabetes-induced phosphorylation of p38 MAPK and its downstream target CREB was also inhibited by the ASO. Our results strongly suggest that blocking CTGF using a chimeric ASO holds substantial promise for the treatment of DN.-Guha, M., Xu, Z-G., Tung, D., Lanting, L., Natarajan, R. Specific downregulation of connective tissue growth factor attenuates progression of nephropathy in mouse models of type 1 and type 2 diabetes. FASEB J. 21, 3355-3368 (2007)
Diabetologia, 2005
Aims/hypothesis: We quantified the glomerular expression of thrombospondin-1 (THBS1, also known as TSP-1), transforming growth factor beta 1 (TGFB1, also known as TGF-β1) and connective tissue growth factor (CTGF) at each stage of diabetic nephropathy. We also examined the roles of THBS1 and CTGF in mediating high-glucose-and glycated-albumin-induced synthesis of the matrix protein, fibronectin, by mesangial cells. Methods: THBS1, latent and active TGFB1, and CTGF, were detected by immunohistochemistry and in situ hybridisation in biopsies from 19 insulin-dependent diabetic patients with incipient, manifest and advanced diabetic nephropathy, and in 11 control kidneys. Findings were quantified by image analysis. Human mesangial cells were cultured with normal or high glucose, albumin or glycated albumin (Amadori product), +/−THBS1 or CTGF antisense oligonucleotides, or with peptide W, an inhibitor of TGFB1 bioactivation by THBS1. Proteins were measured by western blot analysis or ELISA. Results: In glomeruli of normal kidneys, mRNA and protein levels for THBS1, latent-TGFB1 and CTGF were low. They were increased in the incipient stage of diabetic nephropathy, predominantly in mesangial areas, with further increases at later stages of the disease. Little or no active TGFB1 immunostaining was detected prior to manifest diabetic nephropathy. In contrast to high-glucose conditions, increases in fibronectin synthesis that were stimulated by glycated albumin were not dependent on THBS1 activation of latent TGFB1. However, increased fibronectin synthesis in both conditions required CTGF. Conclusions/interpretation: Increased glomerular expression of all three factors occurs from the earliest stage of diabetic nephropathy. In contrast to THBS1, CTGF is required for mesangial synthesis of fibronectin stimulated by high glucose or glycated albumin, and is thus a potential therapeutic target.
Establishment of a Diabetic Mouse Model with Progressive Diabetic Nephropathy
The American Journal of Pathology, 2005
Although diabetic animal models exist, no single animal model develops renal changes identical to those seen in humans. Here we show that transgenic mice that overexpress inducible cAMP early repressor (ICER I␥) in pancreatic  cells are a good model to study the pathogenesis of diabetic nephropathy. Although ICER I␥ transgenic mice exhibit extremely high blood glucose levels throughout their lives, they survive long enough to develop diabetic nephropathy. Using this model we followed the progress of diabetic renal changes compared to those seen in humans. By 8 weeks of age, the glomerular filtration rate (GFR) was already increased, and glomerular hypertrophy was prominent. At 20 weeks, GFR reached its peak, and urine albumin excretion rate was elevated. Finally, at 40 weeks, diffuse glomerular sclerotic lesions were prominently accompanied by increased expression of collagen type IV and laminin and reduced expression of matrix metalloproteinase-2. Nodular lesions were absent, but glomerular basement membrane thickening was prominent. At this point, GFR declined and urinary albumin excretion rate increased, causing a nephrotic state with lower serum albumin and higher serum total cholesterol. Thus, similar to human diabetic nephropathy, ICER I␥ transgenic mice exhibit a stable and progressive phenotype of diabetic kidney disease due solely to chronic hyperglycemia without other modulating factors.
Progression of diabetic nephropathy
American Journal of Kidney Diseases, 2003
Diabetic nephropathy, a kidney disease caused by diabetes, is the most devastating and money-consuming complication in patients with diabetes throughout the world. The cardinal lesion of diabetic nephropathy resides in renal glomeruli and is called diabetic glomerulosclerosis. Hyperglycemia is responsible for the development and progression of diabetic nephropathy through metabolic derangements, including increased oxidative stress, renal polyol formation, activation of protein kinase C (PKC)-mitogen-activated protein kinases (MAPKs), and accumulation of advanced glycation end products, as well as such hemodynamic factors as systemic hypertension and increased intraglomerular pressure. We examined whether inhibition of the PKC-MAPK pathway could inhibit functional and pathological abnormalities in glomeruli from diabetic animal models and cultured mesangial cells exposed to high glucose condition and/or mechanical stretch. Direct inhibition of PKC by PKC beta inhibitor prevented albuminuria and mesangial expansion in db/db mice, a model of type 2 diabetes. We also found that inhibition of MAPK by PD98059, an inhibitor of MAPK, or mitogen-activated extracellular regulated protein kinase kinase prevented enhancement of activated protein-1 (AP-1) DNA binding activity and fibronectin expression in cultured mesangial cells exposed to mechanical stretch in an in vivo model of glomerular hypertension. These findings highlight the important role of PKC-MAPK pathway activation in mediating the development and progression of diabetic nephropathy.
Overview: Combating Diabetic Nephropathy
Journal of the American Society of Nephrology, 2003
Much has been said in the scientific and lay media about the growing epidemic of diabetes around the globe, but individuals and societies should never lose sight of the immeasurable human suffering and the enormous healthcare costs that this epidemic exacts. With the growing population of type 2 diabetes, the prevalence of diabetic nephropathy is on the rise, and there is an urgent need to define the pathophysiologic mechanisms for this devastating disorder. Genetic factors conspire with metabolic and hemodynamic insults to induce renal injury in susceptible individuals. In the current issue of the Journal of the American Society of Nephrology, four authoritative papers provide a balanced overview of the pathogenesis of the disease along with a comprehensive update on the clinical aspects and current management of diabetic nephropathy. Only by translating the new understanding of diabetic nephropathy into medical practice and implementing widespread clinical guidelines will we ever ensure that all at-risk patients receive the ideal care to stem the epidemic and stop nephropathy in its tracks.
TGF-β signaling in diabetic nephropathy: An update
Diabetic Nephropathy
Diabetic nephropathy (DN) is a common complication in patients with diabetes and the leading cause of end-stage renal disease. Accumulating evidence shows that transforming growth factor beta-1 (TGF-β1) is a key mediator in the pathogenesis of DN. TGF-β1 binds to its receptors to activate canonical and noncanonical downstream signaling pathways to exert its biological activities. Among them, canonical Smad signaling is the major pathway responsible for the development of DN. In addition to TGF-β1, many stress molecules, such as advanced glycation end products (AGEs), angiotensin II (Ang II), and C-reactive protein (CRP), can also activate Mothers against decapentaplegic homologs (Smads) via the extracellular signal-regulated kinase (ERK)/p38 mitogen-activated protein kinase (MAPK) cross talk mechanism. Furthermore, TGF-β/Smad signaling can also cross talk with nuclear factor kappa B (NF-κB) signaling to regulate renal inflammation via the induction of IκBα by Smad7. In the context o...