Progression of diabetic nephropathy (original) (raw)
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Diabetes, 2013
Activation of protein kinase C (PKC) has been implicated in the pathogenesis of diabetic nephropathy with proteinuria and peritubular extracellular matrix production. We have previously shown that the PKC isoforms α and β mediate different cellular effects. PKC-β contributes to hyperglycemia-induced renal matrix production, whereby PKC-α is involved in the development of albuminuria. We further tested this hypothesis by deletion of both isoforms and used a PKC inhibitor. We analyzed the phenotype of nondiabetic and streptozotocin (STZ)-induced diabetic homozygous PKC-α/β double-knockout mice (PKC-α/β−/−). After 8 weeks of diabetes mellitus, the high-glucose–induced renal and glomerular hypertrophy as well as transforming growth factor-β1) and extracellular matrix production were diminished in the PKC-α/β−/− mice compared with wild-type controls. Urinary albumin/creatinine ratio also was significantly reduced, however, it was not completely abolished in diabetic PKC-α/β−/− mice. Trea...
Diabetes, 2007
The protein kinase C (PKC)-β isoform has been implicated to play a pivotal role in the development of diabetic kidney disease. We tested this hypothesis by inducing diabetic nephropathy in PKC-β–deficient (PKC-β−/−) mice. We studied nondiabetic and streptozotocin-induced diabetic PKC-β−/− mice compared with appropriate 129/SV wild-type mice. After 8 weeks of diabetes, the high-glucose–induced renal and glomerular hypertrophy, as well as the increased expression of extracellular matrix proteins such as collagen and fibronectin, was reduced in PKC-β−/− mice. Furthermore, the high-glucose–induced expression of the profibrotic cytokine transforming growth factor (TGF)-β1 and connective tissue growth factor were significantly diminished in the diabetic PKC-β−/− mice compared with diabetic wild-type mice, suggesting a role of the PKC-β isoform in the regulation of renal hypertrophy. Notably, increased urinary albumin-to-creatinine ratio persisted in the diabetic PKC-β−/− mice. The loss of...
Diabetologia, 2003
Aims/hypothesis To verify whether individual susceptibility to diabetic nephropathy resides in an intrinsic difference in Protein Kinase C (PKC) activity. Methods We compared the effect of different glucose concentrations on PKC activity, PKC isoform expression and diacylglycerol (DAG) content in cultured fibroblasts from 14 Type 1 diabetic patients who developed nephropathy with those in cells from 14 patients without nephropathy. We recruited 14 normal subjects as control patients. Forearm skin fibroblasts were cultured in either normal (5 mmol/l) or high (20 mmol/l) glucose concentrations. Results In normal glucose, in situ PKC activity was higher in Type 1 patients with nephropathy (10.1±1.4 pmol/min/mg protein; p<0.01) than in those without (6.8±0.8) and the normal control subjects (6.3±0.5). This difference was due to increased concentrations of PKCα isoform in the membrane fraction of fibroblasts from patients with nephropathy. DAG content was also higher in cells from Type 1 patients with nephropathy. Incubation in high glucose concentration caused a further increase in PKC activity and DAG content in quiescent fibroblasts from patients with diabetic nephropathy, with no significant changes in cells from diabetic patients without nephropathy and normal control subjects. Conclusion/interpretation Differences in PKC activation could contribute to the individual susceptibility to renal damage in Type 1 diabetic patients.
BMK1 is activated in glomeruli of diabetic rats and in mesangial cells by high glucose conditions
Kidney International, 2004
Background. High glucose causes renal cell injury through various signal transduction pathways, including mitogenactivated protein (MAP) kinases cascades. Big MAP kinase 1 (BMK1), also known as extracellular signal-regulated kinase 5 (ERK5), is a recently identified MAP kinase family member and was reported to be sensitive to osmotic and oxidative stress. However, the role of BMK1 in diabetic nephropathy has not been elucidated yet.
The FASEB Journal, 2000
Activation of protein kinase C (PKC) is implicated as an important mechanism by which diabetes causes vascular complications. We have recently shown that a PKC  inhibitor ameliorates not only early diabetes-induced glomerular dysfunction such as glomerular hyperfiltration and albuminuria, but also overexpression of glomerular mRNA for transforming growth factor 1 (TGF-1) and extracellular matrix (ECM) proteins in streptozotocin-induced diabetic rats, a model for type 1 diabetes. In this study, we examined the long-term effects of a PKC  inhibitor on glomerular histology as well as on biochemical and functional abnormalities in glomeruli of db/db mice, a model for type 2 diabetes. Administration of a PKC  inhibitor reduced urinary albumin excretion rates and inhibited glomerular PKC activation in diabetic db/db mice. Administration of a PKC  inhibitor also prevented the mesangial expansion observed in diabetic db/db mice, possibly through attenuation of glomerular expression of TGF- and ECM proteins such as fibronectin and type IV collagen. These findings provide the first in vivo evidence that the long-term inhibition of PKC activation in the renal glomeruli can ameliorate glomerular pathologies in diabetic state, and thus suggest that a PKC  inhibitor might be an useful therapeutic strategy for the treatment of diabetic nephropathy.
Involvement of extracellular signal-regulated kinase and p38 in human diabetic nephropathy
American Journal of Kidney Diseases, 2005
Background: The involvement of mitogen-activated protein kinase (MAPK) in human diabetic nephropathy has not been fully investigated. Methods: The presence of cells positive for the phosphorylated MAPK family (phosphorylated extracellular signal-regulated kinase [p-ERK], phosphorylated p38MAPK [p-p38MAPK]) was investigated immunohistochemically in kidneys of 30 patients with diabetic nephropathy. In addition, 10 patients with minimal change nephrotic syndrome, 10 patients with thin basement membrane disease, and 5 patients with benign nephrosclerosis were studied as disease controls. The presence of activated nuclear factor-B (p65)-positive cells also was evaluated in kidney specimens. Results: In patients with diabetic nephropathy, pERK , p-p38MAPK, and p65 were observed in mesangial cells, endothelial cells, podocytes, tubular epithelial cells, and mononuclear infiltrates in interstitium. Numbers of pERK -, p-p38MAPK-, and p65-positive cells in both glomeruli and interstitium in patients with diabetic nephropathy were higher than those in controls. In particular, the number of glomerular pERK positive cells in patients with diabetic nephropathy increased in accordance with the progression of glomerular lesions and correlated well with the number of glomerular p65-positive cells (r ؍ 0.654; P < 0.01; n ؍ 30). Conversely, the number of p-p38MAPK-positive cells in glomeruli did not correlate with glomerular lesions. However, the number of tubulointerstitial p-p38MAPK-positive cells in patients with diabetic nephropathy reflected the severity of tubulointerstitial lesions, and numbers of those in the interstitium increased with good correlation to numbers of tubulointerstitial p65-positive cells (r ؍ 0.757; P < 0.01; n ؍ 30) and interstitial CD68-positive macrophages (r ؍ 0.647; P < 0.05; n ؍ 30) and urinary monocyte chemoattractant protein-1 levels (r ؍ 0.605; P < 0.05; n ؍ 30). Conclusion: These results suggest that MAPK phosphorylation contributes to human diabetic nephropathy. In particular, ERK and p38MAPK may be distinctly involved in glomerular and tubulointerstitial lesions in human diabetic nephropathy.
Journal of The American Society of Nephrology - J AMER SOC NEPHROL, 2007
Protein kinase C (PKC), a family of 12 distinct serine-threonine kinases, is an important intracellular signaling pathway involved in various cellular functions, such as proliferation, hypertrophy, apoptosis, and adhesion. PKC-, a novel PKC isoform that is activated in the diabetic kidney, has been demonstrated to have a central role in the underlying signaling infrastructure of myocardial ischemia and hypertrophy. The renal phenotype of PKC-؊/؊ mice was studied with regard to renal hypertrophy and fibrosis. PKC-؊/؊ deficient knockout mice were generated and then killed after 6, 16, and 26 wk of life. Kidney/body weight ratio did not show any significant group difference compared with appropriate wild-type controls. Urinary albumin/creatinine ratio remained normal in wild-type mice, whereas PKC-؊/؊ mice after 6 and 16 wk showed elevated albuminuria. Masson-Goldner staining revealed that tubulointerstitial fibrosis and mesangial expansion were significantly increased in PKC-؊/؊ mice. However, this profibrotic phenotype was not observed in other organs, such as liver and lung. Immunohistochemistry of the kidneys from PKC-؊/؊ mice showed increased renal fibronectin and collagen IV expression that was further aggravated in the streptozotocin-induced diabetic stress model. Furthermore, TGF- 1 , phospho-Smad2, and phospho-p38 mitogen-activate protein kinase expression was increased in PKC-؊/؊ mice, suggesting a regulatory role of PKCin TGF- 1 and its signaling pathway in the kidney. These results indicate that deletion of PKC-mediates renal fibrosis and that TGF-1 and its signaling pathway might be involved. Furthermore, these data suggest that activation of PKCin the diabetic state may rather represent a protective response to injury than be a mediator of renal injury.
Hypertension Research, 2003
Although it is known that diabetic nephropathy is accelerated by hypertension, the mechanisms involved in this process are not clear. In this study we aimed to clarify these mechanisms using male Wistar fatty rats (WFR) as a type 2 diabetic model and male Wistar lean rats (WLR) as a control. Each group was fed a normal or high sodium diet from the age of 6 to 14 weeks. We determined the blood pressure and urinary albumin excretion (UAE). At the end of the study, the expressions of mitogen-activated protein kinases (MAPK) and transforming growth factor-1 (TGF-1) were examined in the isolated glomeruli by Western blot analysis, and the number of glomerular lesions was determined by conventional histology. High sodium load caused hypertension and a marked increase in UAE in the WFR but not in the WLR. Glomerular volume was increased in the hypertensive WFR. There was no difference among the four groups in the expression of c-Jun-NH2-terminal kinase (JNK). In contrast, the expressions of extracellular signal-regulated kinase 1/2 (ERK1/2) and its upstream regulator, MAPK/ERK kinase 1 (MEK1), were augmented in the hypertensive WFR. Expression of p38 MAPK was increased in the normotensive WFR, and further enhanced in the hypertensive WFR. Moreover, administration of high sodium load to WFR augmented the expression of TGF-1. In conclusion, systemic hypertension in WFR accelerates the diabetic nephropathy in type 2 diabetes via MEK-ERK and p38 MAPK cascades. TGF-1 is also involved in this mechanism.