Angiotensin II blockade prevents hyperglycemia-induced activation of JAK and STAT proteins in diabetic rat kidney glomeruli (original) (raw)
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Role of the JAK/STAT signaling pathway in diabetic nephropathy
AJP: Renal Physiology, 2005
Excessive cellular growth is a major contributor to pathological changes associated with diabetic nephropathy. In particular, high glucose-induced growth of glomerular mesangial cells is a characteristic feature of diabetes-induced renal complications. Glomerular mesangial cells respond to traditional growth factors, although in diabetes this occurs in the context of an environment enriched in both circulating vasoactive mediators and high glucose. For example, the vasoactive peptide ANG II has been implicated in the pathogenesis of diabetic renal disease, and recent findings suggest that high glucose and ANG II activate intracellular signaling processes, including the polyol pathway and generation of reactive oxygen species. These pathways activate the Janus kinase (JAK)/signal transducers and activators of transcription (STAT) signaling cascades in glomerular mesangial cells. Activation of the JAK/STAT signaling cascade can stimulate excessive proliferation and growth of glomerula...
Enhanced Expression of JAK-STAT Pathway Members in Human Diabetic Nephropathy
2008
Objective. Glomerular mesangial expansion and podocyte loss are important early features of diabetic nephropathy (DN) whereas tubulointerstitial injury and fibrosis are critical for progression of DN to kidney failure. Therefore, we analyzed the expression of genes in glomeruli and tubulointerstitium in kidney biopsies from DN patients to identify pathways that may be activated in humans but are not in murine models of DN that fail to progress to glomerulosclerosis, tubulointerstitial fibrosis and kidney failure. Research Design and Methods. Kidney biopsies were obtained from 74 patients (controls, early and progressive type 2 DN). Glomerular and tubulointerstitial mRNAs were microarrayed, followed by bioinformatics analyses. Gene expression changes were confirmed by real-time RT-PCR and immunohistological staining. Samples from db/db C57BLKS and streptozotocin-DBA/2J mice, commonly studied murine models of DN, were analyzed. Results. In human glomeruli and tubulointerstitial sample...
Journal of Endocrinology, 2002
Clinical and animal studies have shown that treatment with angiotensin-converting enzyme (ACE) inhibitors or angiotensin II (Ang II) receptor antagonists slows the progression of nephropathy in diabetes, indicating that Ang II plays an important role in its development. We have reported previously that insulin inhibits the stimulatory effect of high glucose levels on angiotensinogen (ANG) gene expression in rat immortalized renal proximal tubular cells (IRPTCs) via the mitogen-activated protein kinase (p44/42 MAPK) signal transduction pathway. We hypothesize that the suppressive action of insulin on ANG gene expression might be attenuated in renal proximal tubular cells (RPTCs) of rats with established diabetes. Two groups of male adult Wistar rats were studied: controls and streptozotocin (STZ)-induced diabetic rats at 2, 4, 8 and 12 weeks post-STZ administration. Kidney proximal tubules were isolated and cultured in either normal glucose (i.e. 5 mM) or high glucose (i.e. 25 mM) me...
Role of Angiotensin-(1-7) on Renal Hypertrophy in Streptozotocin-Induced Diabetes Mellitus
Pharmacology & Pharmacy, 2016
Participation of angiotensin II in chronic kidney diseases including diabetic nephropathy (DN) has been extensively described. Similarly, several studies support a protective role for angiotensin-(1-7). However, other studies suggest that some of the cellular effects of angiotensin-(1-7) may be deleterious. The objective of this study was to determine the role of exogenous angiotensin-(1-7) on renal hypertrophy development in rats with streptozotocin-induced diabetes. A control group and three groups of rats with streptozotocin-induced diabetes: untreated diabetic rats, diabetic rats treated with captopril, and diabetic rats treated with angiotensin-(1-7), were studied. After two weeks of treatment, the kidneys were removed under anesthesia with pentobarbital. The kidneys were weighed and the renal cortex was separated for analysis of AT 1 R, TGF-β 1 , MASR, and ACE2 expression by western blot. Rats in the three groups with diabetes had hyperglycemia, increased food and water consumption, and higher urinary volume than control rats. Treatment with captopril or angiotensin-(1-7) reversed streptozotocin-induced renal hypertrophy, measured by kidney weight, protein/DNA ratio in renal cortex, glomerular area, or proximal tubular cells area, proteinuria, and creatinine clearance reduction. AT 1 R, TGF-β 1 , and MAS receptor expression in renal cortex of diabetic rats increased significantly as compared to controls (p < 0.05); treatment with captopril or angiotensin-(1-7) reversed such increments. ACE2 in the renal cortex decreased in diabetic rats, but it was increased after treatment with captopril or angiotensin-(1-7). These findings suggest that exogenous administration of angiotensin-(1-7) may be renoprotective in early stages of diabetes mellitus.
Role of angiotensin II in diabetic nephropathy
Kidney International, 2000
Role of angiotensin II in diabetic nephropathy. Considerable [8-15] of matrix components are responsible for matrix evidence suggests that the intrarenal renin-angiotensin system accumulation. plays an important role in diabetic nephropathy. Angioten-Mediators of mesangial matrix expansion in diabetic sin-converting enzyme (ACE) inhibitors and angiotensin II nephropathy have not been fully identified. A prominent (Ang II) receptor blockers (ARBs) can attenuate progressive role for the peptide angiotensin II (Ang II) has been glomerulosclerosis in disease models and can slow disease progression in humans. Because agents that interfere with Ang II suggested by experimental and clinical evidence indicataction may decrease glomerular injury without altering glomering that angiotensin-converting enzyme (ACE) inhibiular pressures, it has been suggested that Ang II has direct tors and angiotensin receptor blockers (ARBs) have reeffects on glomerular cells to induce sclerosis independent of noprotective effects that cannot be entirely explained by its hemodynamic actions. To study nonhemodynamic effects of Ang II on matrix metabolism, many investigators have used their blood pressure lowering effects [16-19]. The ACE cell culture systems. Glucose and Ang II have been shown to inhibitor enalapril inhibits gene expression of ECM proproduce similar effects on renal cells in culture. For instance, teins in diabetic rats [20], suggesting that Ang II is imporincubation of mesangial cells in high-glucose media or in the tant in the development of glomerulosclerosis and that presence of Ang II stimulates matrix protein synthesis and preventing its formation can decrease matrix synthesis. inhibits degradative enzyme (e.g., collagenase, plasmin) activity. Glucose and Ang II also can inhibit proximal tubule pro-However, in studies in whole animals or humans, it is teinases. Glucose increases expression of the angiotensinogen difficult to separate the effects of blood pressure reducgene in proximal tubule cells and Ang II production in primary tion from other biochemical effects of these agents. mesangial cell culture, which indicates that high glucose itself Use of cell culture obviates these problems because can activate the renin-angiotensin system. The effects of glucose and Ang II on mesangial matrix metabolism may be medi
Angiotensin II and endothelin-1 augment the vascular complications of diabetes via JAK2 activation
AJP: Heart and Circulatory Physiology, 2007
word count: 250 Article word count: 3,516 Abstract The JAK/STAT pathway is activated in vitro by angiotensin II (ANG II) and endothelin-1 (ET-1), which are implicated in the development of diabetic complications. We hypothesized that ANG II and ET-1 activate the JAK/STAT pathway in vivo to participate in the development of diabetic vascular complications. Using male Sprague-Dawley rats we performed a time course study (days 7, 14 and 28 post-STZ injection) to determine changes in phosphorylation of JAK2, STAT1 and STAT3 in thoracic aorta using standard Western blot techniques. On day 7 there was no change in phosphorylation of JAK2, STAT1 and STAT3. Phosphorylation of JAK2, STAT1 and STAT3 significantly increased on days 14 and 28 and was inhibited by treatment with candesartan (AT 1 receptor antagonist, 10 mg/kg/day, orally in drinking water), atrasentan (ET A receptor antagonist, 10 mg/kg/day, orally in drinking water) and AG490 (JAK2 inhibitor, 5 mg/kg/day, ip). On day 28, treatment with all inhibitors prevented the significant increase in systolic blood pressure (tail cuff) of STZ-induced diabetic rats (SBP mmHg: 157+ 9.0, 130+3.3, 128+6.8, 131+10.4, STZ, STZ-candesartan, STZatrasentan and STZ-AG490 treated respectively). In isolated tissue bath studies, diabetic rats displayed impaired endothelium-dependent relaxation in aorta (maximal relaxation: 95.3%+ 3.0, 92.6% + 7.4, 76.9% + 12.1, 38.3% + 13.1; Sham, Sham & AG490, STZ & AG490, STZ respectively). Treatment of rats with AG490 restored endotheliumdependent relaxation in aorta from diabetic rats at 14 and 28 days of treatment. These results demonstrate that JAK2 activation in vivo participates in the development of vascular complications associated with STZ-induced diabetes.