Lumbrokinase attenuates diabetic nephropathy through regulating extracellular matrix degradation in Streptozotocin-induced diabetic rats

Sun, Huili; Ge, Na; Shao, Mumin; Cheng, Xiaoyan; Li, Yue; Li, Shunmin; Shen, Jiangang

doi:10.1016/j.diabres.2013.01.012

Cited by 28 publications

(36 citation statements)

References 39 publications

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“…Therefore, renal tissue of diabetic animals subjected to nephrectomy demonstrated slight, segmental and focal tubulointerstitial changes. In diabetic nephropathy, cells accumulate glycogen and collagen fibers in the mesangial region and in the basal membrane showing glomerulosclerosis, tubulointerstitial fibrosis, mesangial expansion, deposits of extracellular matrix, and tubulointerstitial changes (28,29). Therefore, this study reproduced the synergism found in the physiopathology of diabetic nephropathy by means of hemodynamic and oxidative mechanisms associated with histological changes.…”

Section: Discussionsupporting

confidence: 67%

The role of oxidative stress in streptozotocin-induced diabetic nephropathy in rats

Fernandes

Cordeiro

Watanabe

et al. 2016

Arch. Endocrinol. Metab.

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Objective: The objective of this study was to evaluate the role of oxidative stress in an experimental model of streptozotocin-induced diabetic nephropathy in rats. Materials and methods: Wistar, adult, male rats were used in the study. Animals were divided in the following groups: Citrate (control, citrate buffer 0.01M, pH 4.2 was administrated intravenously -i.v -in the caudal vein), Uninephrectomy+Citrate (left uninephrectomy-20 days before the study), DM (streptozotocin, 65 mg/kg, i.v, on the 20 th day of the study), Uninephrectomy+DM. Physiological parameters (water and food intake, body weight, blood glucose, kidney weight, and relative kidney weight); renal function (creatinine clearance), urine albumin (immunodiffusion method); oxidative metabolites (urinary peroxides, thiobarbituric acid reactive substances, and thiols in renal tissue), and kidney histology were evalua ted. Results: Polyphagia, polydipsia, hyperglycemia, and reduced body weight were observed in diabetic rats. Renal function was reduced in diabetic groups (creatinine clearance, p < 0.05). Uninephrectomy potentiated urine albumin and increased kidney weight and relative kidney weight in diabetic animals (p < 0.05). Urinary peroxides and thiobarbituric acid reactive substances were increased, and the reduction in thiol levels demonstrated endogenous substrate consumption in diabetic groups (p < 0.05). The histological analysis revealed moderate lesions of diabetic nephropathy. Conclusion: This study confirms lipid peroxidation and intense consumption of the antioxidant defense system in diabetic rats. The association of hyperglycemia and uninephrectomy resulted in additional renal injury, demonstrating that the model is adequate for the study of diabetic nephropathy. Arch Endocrinol Metab. 2016;60(5):443-9

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Section: Discussionsupporting

confidence: 67%

The role of oxidative stress in streptozotocin-induced diabetic nephropathy in rats

Fernandes

Cordeiro

Watanabe

et al. 2016

Arch. Endocrinol. Metab.

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“…Insufficient MMP-2 and MMP-9 is considered to be a contributor of ECM accumulation (11). Whether C-peptide regulates MMP-2 and MMP-9 to reverse fibrosis is unclear.…”

Section: Discussionmentioning

confidence: 99%

“…Generally, MMP-2 and MMP-9 are involved in tumor metastasis (6,10). Furthermore, it has been shown that insufficient MMP-2 and MMP-9 may be a contributor of ECM accumulation in DN (11). However, the expression levels of MMP-2 and MMP-9 in DN remain controversial, and even short-and long-term hyperglycemia may exert differential effects (8,(12)(13)(14).…”

Section: Introductionmentioning

confidence: 99%

C-peptide exhibits a late induction effect on matrix metallopeptidase-9 in high glucose-stimulated rat mesangial cells

Wang

et al. 2016

Experimental and Therapeutic Medicine

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Abstract. Insufficient matrix metalloproteinase (MMP)-9 and MMP-2 is considered to be a contributor of extracellular matrix (ECM) accumulation in diabetic nephropathy (DN). C-peptide can reverse fibrosis, thus exerting a beneficial effect on DN. Whether C-peptide induces MMP-9 and MMP-2 to reverse ECM accumulation is not clear. In the present study, in order to determine ECM metabolism, rat mesangial cells were treated with high glucose (HG) and C-peptide intervention, then the early and late effects of C-peptide on HG-affected MMP-9 and MMP-2 were evaluated. Firstly, it was confirmed that HG mainly suppressed MMP-9 expression levels. Furthermore, C-peptide treatment induced MMP-9 expression at 6 h and suppressed it at 24 h, revealing the early dual effects of C-peptide on MMP-9 expression. Subsequently, significant increase in MMP-9 expression at 72, 96 and 120 h C-peptide treatment was observed. These changes in MMP-9 protein content confirmed its expression changes following late C-peptide treatment. Furthermore, at 96 and 120 h C-peptide treatment reversed the HG-inhibited MMP-9 secretion, further indicating the late induction effect of C-peptide on MMP-9. The present results demonstrated that C-peptide exerted a late induction effect on MMP-9 in HG-stimulated rat mesangial cells, which may be associated with the underlying mechanism of C-peptide's reversal effects on DN. IntroductionDiabetic nephropathy (DN), the leading cause of end stage renal disease, is the major cause of mortality in type 1 diabetes mellitus (DM) and the second most severe complications in type 2 diabetes (1,2). Deposition of extracellular matrix (ECM) in mesangial areas is a feature of DN, and mesangial cells have been proposed to be the determinant of ECM accumulation (3,4). However, the mechanism underlying ECM accumulation in DN is not fully clarified.Matrix metalloproteinases (MMPs) are a family of zinc-dependent endopeptidases that can degrade numerous types of ECM components (5,6). Among others, MMP-2 basally expresses while MMP-9 is an inducible enzyme, both of which primarily degrade types-I and -IV collagen and laminin, major components of ECM (7-9). Generally, MMP-2 and MMP-9 are involved in tumor metastasis (6,10). Furthermore, it has been shown that insufficient MMP-2 and MMP-9 may be a contributor of ECM accumulation in DN (11). However, the expression levels of MMP-2 and MMP-9 in DN remain controversial, and even short-and long-term hyperglycemia may exert differential effects (8,(12)(13)(14). As an inducible enzyme, MMP-9 may be more easily affected in patients with DN (15). Therefore, the changes of MMP-2, and particularly MMP-9, for high glucose (HG) stimulation require clarification.C-peptide is the linker between the A-chain and B-chain of insulin. Lack of C-peptide along with insulin is the primary feature of type 1 DM and late stage of type 2 DM (16). C-peptide has been found to have unique beneficial effects on DN, attenuating glomerular and tubular injury (17)(18)(19). Physiological concentration of C-peptide ca...

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“…18 Of the MMPs, the gelatinases MMP-2 and MMP-9 are primarily involved in the pathogenesis of DN, with significant reductions in both their expression and activity in DN. 15,19 However, some reports indicate biphasic modulation of MMP-9, with initial activation followed by a decline in later stages of DN. 20 In another study, similar biphasic response is reported for activity of superoxide dismutase and catalase in pathogenesis of acute kidney injury induced by cisplatin and also hyperlipidimia induced by high fructose diet.…”

Section: Introductionmentioning

confidence: 99%

“…[12][13][14] These changes are attributed to increased synthesis or decreased degradation of the ECM. 15 Persistent hyperglycemia produces extra advanced glycation end-products (AGEs) and activates protein kinase C (PKC), further increasing the expression of vascular endothelial growth factor (VEGF), transforming growth factor (TGF)-β and connective tissue growth factor (CTGF). These changes result in glomerular hypertrophy, increased permeability to macromolecules, albuminuria, basement membrane thickening, and cast deposition.…”

Section: Introductionmentioning

confidence: 99%

An extract of Pueraria tuberosa tubers attenuates diabetic nephropathy by upregulating matrix metalloproteinase‐9 expression in the kidney of diabetic rats

Tripathi

Shukla

Pandey

et al. 2016

Journal of Diabetes

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Background: Currently, no drug is available to directly target the signaling molecules involved in the pathogenesis of diabetic nephropathy (DN); only antihypertensive and antidiabetic drugs are in clinical use. In the present study, the therapeutic effects of a active fraction of tubers from Pueraria tuberosa (hereafter referred to as PTY-2) were investigated in streptozotocin (STZ)-diabetic rats with DN, with particular emphasis on its effects on extracellular matrix (ECM) accumulation and matrix metalloproteinase (Mmp)-9 expression in kidney tissue. Methods: Rats were injected with 55 mg/kg, i.p., STZ. After 40 days, rats were divided into groups as follows (n = 6 per group): Group 1, age-matched rats not injected with STZ (non-diabetic control); Group 2, STZ-diabetic DN rats; and Group 3, PTY-2 (30 mg/100 g, p.o.)-treated DN rats. After 20 days treatment, the effects of PTY-2 on serum urea and creatinine concentrations, urinary levels of glucose, creatinine, protein, and ketone bodies, and urine pH were determined. Kidney tissue was evaluated for Mmp-9 expression and histological changes. Results: Blood glucose, serum urea, creatinine, and urine protein levels were significantly higher, and creatinine clearance was significantly lower, in Group 2 versus Group 1 rats. There was a higher degree of glomerulosclerosis, expansion of the mesangial matrix, and excess ECM deposition and eosinophilic casts in kidneys from Group 2 versus Group 1 rats. Furthermore, Mmp-9 activity and expression were significantly reduced in kidney homogenate of Group 2 versus Group 1 rats. Interestingly, PTY-2 treatment significantly reversed all these changes in DN rats. Conclusion: Treatment of DN rats with PTY-2 significantly attenuated the severity of DN by increasing the expression and activity of Mmp-9, consequently degrading the ECM accumulated in kidney tissue.

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Lumbrokinase attenuates diabetic nephropathy through regulating extracellular matrix degradation in Streptozotocin-induced diabetic rats

Cited by 28 publications

References 39 publications

The role of oxidative stress in streptozotocin-induced diabetic nephropathy in rats

The role of oxidative stress in streptozotocin-induced diabetic nephropathy in rats

C-peptide exhibits a late induction effect on matrix metallopeptidase-9 in high glucose-stimulated rat mesangial cells

An extract of Pueraria tuberosa tubers attenuates diabetic nephropathy by upregulating matrix metalloproteinase‐9 expression in the kidney of diabetic rats

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