Early intensive insulin therapy attenuates the p38 pathway in the renal cortex and indices of nephropathy in diabetic rats

Fang, Donghong; Guan, Hongyu; Liu, Juan; Wei, Guohong; Ke, Weijian; Yao, Bin; Xiao, Hang; Li, Yanbing

doi:10.1507/endocrj.ej11-0057

Cited by 14 publications

(12 citation statements)

References 22 publications

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“…Increased renal cortical p38 activity in diabetic rats could be attenuated by improved glycemic control [26]. Treatment with zerumbone also reduced the elevated levels of p38 in the kidneys of STZ-diabetic rats, suggesting that the renal protective effect of zerumbone might be also related with the modulation of p38 signal transduction to attenuate hyperglycemia-affected renal dysfunction.…”

Section: Discussionmentioning

confidence: 99%

Zerumbone, a tropical ginger sesquiterpene, ameliorates streptozotocin-induced diabetic nephropathy in rats by reducing the hyperglycemia-induced inflammatory response

et al. 2013

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BackgroundZerumbone is one of the pungent constituents of Zingiber zerumbet (L) Smith (Zingiberaceae family). The aim of the present study was to examine the effects of zerumbone in rats with streptozotocin-induced diabetic nephropathy (DN).MethodsDiabetic rats were treated orally with zerumbone (20 or 40 mg/kg/day) for 8 weeks. Changes in renal function-related parameters in plasma and urine were analyzed at the end of the study. Kidneys were isolated for pathology histology, immunohistochemistry, and Western blot analyses.ResultsDiabetic rats exhibited renal dysfunction, as evidenced by reduced creatinine clearance, increased blood glucose, blood urea nitrogen and proteinuria, along with marked elevation in the ratio of kidney weight to body weight, that were reversed by zerumbone. Zerumbone treatment was found to markedly improve histological architecture in the diabetic kidney. Hyperglycemia induced p38 mitogen-activated protein kinase activation, leading to increased infiltration of macrophages and increased levels of interleukin (IL)-1, IL-6 and tumor necrosis factor-α. All of the above abnormalities were reversed by zerumbone treatment, which also decreased the expression of intercellular adhesion molecule-1, monocyte chemoattractant protein-1, transforming growth factor-β1 and fibronectin in the diabetic kidneys.ConclusionsThe beneficial effect of zerumbone in rats with DN is at least in part through antihyperglycemia which was accompanied by inhibition of macrophage infiltration via reducing p38 mediated inflammatory response.

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Section: Discussionmentioning

confidence: 99%

Zerumbone, a tropical ginger sesquiterpene, ameliorates streptozotocin-induced diabetic nephropathy in rats by reducing the hyperglycemia-induced inflammatory response

et al. 2013

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“…Persistent oxidative stress30, glomerular basement membrane accumulation31, expression of extracellular matrix proteins1532, and increased p38 MAPK activity33 have been confirmed after the normalization of glucose levels in different in vitro and in vivo models. Additionally, epigenetic mechanisms operating in the pathogenesis of DKD are emphasized as key events underlying metabolic memory, particularly due to their long-term persistence34.…”

Section: Discussionmentioning

confidence: 91%

Sustained kidney biochemical derangement in treated experimental diabetes: a clue to metabolic memory

Oliveira

Bobadilla

et al. 2017

Sci Rep

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The occurrence of biochemical alterations that last for a long period of time in diabetic individuals even after adequate handling of glycemia is an intriguing phenomenon named metabolic memory. In this study, we show that a kidney pathway is gradually altered during the course of diabetes and remains persistently changed after late glycemic control in streptozotocin-induced diabetic rats. This pathway comprises an early decline of uric acid clearance and pAMPK expression followed by fumarate accumulation, increased TGF-β expression, reduced PGC-1α expression, and downregulation of methylation and hydroxymethylation of mitochondrial DNA. The sustained decrease of uric acid clearance in treated diabetes may support the prolonged kidney biochemical alterations observed after tight glycemic control, and this regulation is likely mediated by the sustained decrease of AMPK activity and the induction of inflammation. This manuscript proposes the first consideration of the possible role of hyperuricemia and the underlying biochemical changes as part of metabolic memory in diabetic nephropathy development after glycemic control.

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“…P38, which contributes to the pathogenesis of diabetic nephropathy, is activated in in vivo glomeruli from diabetic rats and in mesangial cells exposed to high glucose. Early intensive insulin treatment prevents the increase in renal cortical P38 activity in diabetic rats, thereby attenuating the pathological changes associated with diabetic nephropathy [16]. These results suggest that P38 could be a therapeutic target for diabetes.…”

Section: Discussionmentioning

confidence: 99%

P38 Plays an Important Role in Glucolipotoxicity-Induced Apoptosis in INS-1 Cells

Zhou

Cai

Han

et al. 2014

Journal of Diabetes Research

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Objectives. The mechanism underlying the regulation of glucolipotoxicity-induced apoptosis by MAPKs was examined in INS-1 cells. Methods. The rat insulinoma cell line INS-1 was cotreated with glucose (30 mM) and palmitic acid (0.2 mM) (GLU+PA). Apoptosis was assessed by cell morphology and detection of PARP cleavage. The activation of MAPKs was examined by Western blotting using specific antibodies against the phosphorylated forms of JNK, ERK1/2, and P38. Results. (1) Live cell imaging studies showed that treatment with GLU+PA for 72 h induced significant cell death, concomitant with PARP-1 cleavage and caspase-3 activation, which peaked at 96 h of treatment. (2) Western blot analysis of the activation of MAPKs during GLU+PA-induced INS-1 cell apoptosis showed that phosphorylation of P38 increased gradually and reached a peak at 96 h, which coincided with PARP-1 cleavage. A transient increase of ERK activation was followed by a rapid decline at 96 h, whereas JNK phosphorylation status remained unchanged in response to GLU+PA. (3) Phosphorylation of insulin receptor substrate (IRS)-2 at 48 h of treatment triggered its degradation, which coincided with P38 activation. (4) Inhibition of P38, but not JNK or ERK, blocked GLU+PA-induced INS-1 cell apoptosis. Conclusions. P38 may be involved in the regulation of glucolipotoxicity-induced apoptosis through the phosphorylation of IRS-2.

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Early intensive insulin therapy attenuates the p38 pathway in the renal cortex and indices of nephropathy in diabetic rats

Cited by 14 publications

References 22 publications

Zerumbone, a tropical ginger sesquiterpene, ameliorates streptozotocin-induced diabetic nephropathy in rats by reducing the hyperglycemia-induced inflammatory response

Zerumbone, a tropical ginger sesquiterpene, ameliorates streptozotocin-induced diabetic nephropathy in rats by reducing the hyperglycemia-induced inflammatory response

Sustained kidney biochemical derangement in treated experimental diabetes: a clue to metabolic memory

P38 Plays an Important Role in Glucolipotoxicity-Induced Apoptosis in INS-1 Cells

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