Hypertension Accelerates Diabetic Nephropathy in Wistar Fatty Rats, a Model of Type 2 Diabetes Mellitus, via Mitogen-Activated Protein Kinase Cascades and Transforming Growth Factor-.BETA.1

Imai, Goro; Satoh, Takeo; Kumai, Toshio; Murao, Mei; Tsuchida, Hiroki; Shima, Yoshinori; Ogimoto, Goichi; Fujino, Tomoya; Kobayashi, Shinichi; Kimura, Kenjiro

doi:10.1291/hypres.26.339

Cited by 23 publications

(14 citation statements)

References 36 publications

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“…5 Likewise, the nephropathy was worsened by a high-sodium diet in Wistar fatty rats, a model of obese diabetes, but not in Wistar lean rats. 30 These findings suggest that some unifying factor(s) related to obesity might be involved in the mechanisms and that salt restriction is critically important in the management of obesity-related disorders, including metabolic syndrome. Although a high-salt diet reduced circulating aldosterone in SHR/cps, this inhibition was blunted in this model as compared with salt-resistant animals ( Figure S1).…”

Section: Discussionmentioning

confidence: 95%

Salt-Induced Nephropathy in Obese Spontaneously Hypertensive Rats Via Paradoxical Activation of the Mineralocorticoid Receptor

et al. 2007

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Abstract-Aldosterone is implicated in the pathogenesis of proteinuria and chronic kidney disease. We previously demonstrated the contribution of elevated serum aldosterone in the early nephropathy of SHR/NDmcr-cp (SHR/cp), a rat model of metabolic syndrome. In the present study, we investigated the effect of salt loading on renal damage in SHR/cps and explored the underlying mechanisms. SHR/cps fed a high-sodium diet for 4 weeks developed severe hypertension, massive proteinuria, and advanced renal lesions. High salt also worsened glomerular podocyte impairment. Surprisingly, selective mineralocorticoid receptor (MR) antagonist eplerenone dramatically ameliorated the salt-induced proteinuria and renal injury in SHR/cps. Although salt loading reduced circulating aldosterone, it increased nuclear MR and expression of aldosterone effector kinase Sgk1 in the kidney. Gene expressions of transforming growth factor-␤1 and plasminogen activator inhibitor-1 were also enhanced in the kidneys of salt-loaded SHR/cps, and eplerenone completely inhibited these injury markers. To clarify the discrepancy between decreased aldosterone and enhanced MR signaling by salt, we further investigated the role of oxidative stress, a putative key factor mediating salt-induced tissue damage. Interestingly, antioxidant Tempol attenuated the salt-evoked MR upregulation and Sgk1 induction and alleviated proteinuria and renal histological abnormalities, suggesting the involvement of oxidative stress in salt-induced MR activation. MR activation by salt was not attributed to increased serum corticosterone or reduced 11␤-hydroxysteroid dehydrogenase type 2 activity. In conclusion, sodium loading exacerbated proteinuria and renal injury in metabolic syndrome rats. Salt reduced circulating aldosterone but caused renal MR activation at least partially via induction of oxidative stress, and eplerenone effectively improved the nephropathy. Key Words: aldosterone Ⅲ mineralocorticoids Ⅲ metabolic syndrome Ⅲ sodium Ⅲ dietary Ⅲ oxidative stress (kidney) Ⅲ chronic kidney disease Ⅲ proteinuria Ⅲ eplerenone S alt plays an important role in the progression of target organ injury, as well as in the pathogenesis of hypertension. Epidemiologic studies revealed that higher sodium intake increases the risk of cardiovascular disease, independent of other risk factors, 1 and causes poor prognosis of renal disease. 2 Experimental animal studies indicated that increased dietary salt promotes renal fibrosis and progression of kidney disease. 3,4 The deleterious effects of salt are, at least partially, independent of blood pressure (BP). 1,2,4 Susceptibility to salt is reported to be augmented in certain disease conditions. For example, high salt exacerbates proteinuria in overweight but not nonoverweight subjects. 5 However, the underlying mechanisms have not been clearly elucidated.Accumulating evidence suggests that aldosterone is an important pathogenetic factor in the progression of renal disease and heart failure. 6 In the kidney, aldosterone was demonstrated to ...

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Section: Discussionmentioning

confidence: 95%

Salt-Induced Nephropathy in Obese Spontaneously Hypertensive Rats Via Paradoxical Activation of the Mineralocorticoid Receptor

et al. 2007

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“…The critical role of TGF-␤1 in diabetes-induced renal cell hypertrophy and renal ECM accumulation, leading to DN, has been extensively addressed (10,19,20,27). Whether diabetic upregulation of renal UII and its receptor is also involved in renal upregulation of TGF-␤1, leading to renal fibrosis and even to DN, remains unclear.…”

Section: Discussionmentioning

confidence: 99%

Diabetes-induced upregulation of urotensin II and its receptor plays an important role in TGF-β1-mediated renal fibrosis and dysfunction

Tian¹,

Cai²,

Qi³

et al. 2008

American Journal of Physiology-Endocrinology and Metabolism

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L. Diabetes-induced upregulation of urotensin II and its receptor plays an important role in TGF-␤1-mediated renal fibrosis and dysfunction. Am J Physiol Endocrinol Metab 295: E1234 -E1242, 2008. First published September 16, 2008 doi:10.1152/ajpendo.90672.2008.-Urotensin II (UII) was identified as the ligand for a novel G protein-coupled receptor, GPR14. UII was found not only to have a potent vasoconstrictive action but also to have profibrotic effects in the heart. The present study was to define whether UII and GPR14 also play important roles in diabetes-induced renal fibrosis and dysfunction. Diabetic rats were induced using streptozotocin, and the rat proximal tubular epithelial cells (NRK-52E) were used for the in vitro mechanism study. Results showed that expression of UII and GPR14 was significantly upregulated at both mRNA and protein levels in the diabetic kidneys compared with controls. The upregulated expressions of UII and GPR14 in the kidney were accompanied by significant increases in the renal profibrotic factor transforming growth factor (TGF)-␤1 expression, the renal extracellular matrix (fibronectin and collagen IV) accumulation, and the renal dysfunction (increases in urinal N-acetyl-␤-D-glucosaminidase content, 24-h urinary retinol-binding protein excretion rate, and decrease in creatinine clearance rate). Exposure of NRK-52E cells to 10 Ϫ8 mol/l UII for 48 h caused a significant increase of TGF-␤1, but not ANG II, production that was GPR14-and calcium-dependent, since GPR14 small-interfering RNA and calcium channel blocker nimodipine or calcium chelator EDTA all could abolish the induction of TGF-␤1 by UII. Furthermore, exposure of NRK-52E cells to TGF-␤1 or ANG II also increased UII and GPR14 mRNA expressions. These results suggested that diabetes-induced upregulation of UII and GPR14, most likely through autocrine and/or paracrine mechanisms, plays an important role in TGF-␤1-mediated renal fibrosis and dysfunction. diabetic nephropathy; G protein-coupled receptor 14; renal extracellular matrix accumulation; streptozotocin diabetic rats; angiotensin II; transforming growth factor-␤1 DIABETIC NEPHROPATHY (DN) is one of the major microvascular complications and also the leading cause of the end-stage renal disease (ESRD). Therefore, to develop an effective approach to delay or halt the pathogenic progression toward ESRD in patients with overt DN is urgent (8,17,19). To understand the mechanisms responsible for the initiation and development of the diabetes-induced renal pathogenesis will help us to develop the effectively preventive or therapeutic approaches for DN (19). Many factors play roles in the pathogenesis of DN; for instance, both transforming growth factor ␤1 (TGF-␤1) and ANG II are important factors to promote the development of DN (10,17,19,27).Urotensin II (UII), an 11-amino acid vasoactive peptide, was identified as the ligand for a novel G protein-coupled receptor, GPR14 (also named as urotensin receptor) (13). UII was found to be a powerful vasoconstrictor with potency gre...

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“…In a variety of animal models, the p38 MAPK pathway has been shown to play an important role in the nephropathy of hypertension and type-II diabetes. For example, saltaccelerated hypertension in the type-II diabetic Wistar fatty rat is associated with renal dysfunction and enhanced activation of p38 MAPK and expression of TGF-h in the kidney [18]. Evidence suggests that p38 MAPK acts in the kidney to transduce the diabetic complications of elevated glucose [19] and stretch in mesangial cells [20].…”

Section: Discussionmentioning

confidence: 99%

Hypertensive target organ damage is attenuated by a p38 MAPK inhibitor: role of systemic blood pressure and endothelial protection

Olzinski

McCafferty

Zhao³

et al. 2005

Cardiovascular Research

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Hypertension Accelerates Diabetic Nephropathy in Wistar Fatty Rats, a Model of Type 2 Diabetes Mellitus, via Mitogen-Activated Protein Kinase Cascades and Transforming Growth Factor-.BETA.1

Cited by 23 publications

References 36 publications

Salt-Induced Nephropathy in Obese Spontaneously Hypertensive Rats Via Paradoxical Activation of the Mineralocorticoid Receptor

Salt-Induced Nephropathy in Obese Spontaneously Hypertensive Rats Via Paradoxical Activation of the Mineralocorticoid Receptor

Diabetes-induced upregulation of urotensin II and its receptor plays an important role in TGF-β1-mediated renal fibrosis and dysfunction

Hypertensive target organ damage is attenuated by a p38 MAPK inhibitor: role of systemic blood pressure and endothelial protection

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