Tumstatin Peptide, an Inhibitor of Angiogenesis, Prevents Glomerular Hypertrophy in the Early Stage of Diabetic Nephropathy

Yamamoto, Yoshihiko; Maeshima, Yohei; Kitayama, Hiroyuki; Kitamura, Shinji; Takazawa, Yuki; Sugiyama, Hiroshi; Yamasaki, Yasushi; Makino, Hírofumi

doi:10.2337/diabetes.53.7.1831

Cited by 168 publications

(165 citation statements)

References 47 publications

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“…Glomerular morphometric analysis demonstrates that diabetic C57BL/6, 129Sv, and CD1 mice develop glomerular hypertrophy, confirming previous studies (19,20) (Fig. 1C).…”

Section: Resultssupporting

confidence: 74%

Renal Fibrosis and Glomerulosclerosis in a New Mouse Model of Diabetic Nephropathy and Its Regression by Bone Morphogenic Protein-7 and Advanced Glycation End Product Inhibitors

et al. 2007

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Diabetic nephropathy is currently the most common cause of end-stage renal disease (ESRD) in the western world. A mouse model for diabetic nephropathy that encompasses the salient features of this disease in the kidney is not available. Here, we report that CD1 mice, in contrast to inbred C57BL/6 and 129Sv strains, develop ESRD associated with prominent tubulointerstitial nephritis and fibrosis within 3 months and die because of diabetic complications by 6 -7 months after a single injection of streptozotocin. Histopathologic lesions observed in these mice mimic human diabetic nephropathy, including glomerular hypertrophy, diffuse glomerulosclerosis, tubular atrophy, interstitial fibrosis, and decreased renal excretory function. Next, we tested the therapeutic efficacy of bone morphogenic protein-7 (BMP-7) and inhibitors of advanced glycation end products (AGEs), aminoguanidine and pyridoxamine, to inhibit and regress the progression of renal disease in diabetic CD1 mice. We demonstrate that although aminoguanidine, pyridoxamine, and BMP-7 significantly inhibit glomerular lesions, BMP-7 is most effective in the inhibition of tubular inflammation and tubulointerstitial fibrosis in these mice. Collectively, our results report a new mouse model for diabetic nephropathy with prominent interstitial inflammation and fibrosis and the selective inhibition of diabetic kidney disease by AGE inhibitors and BMP-7.

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“…Glomerular morphometric analysis demonstrates that diabetic C57BL/6, 129Sv, and CD1 mice develop glomerular hypertrophy, confirming previous studies (19,20) (Fig. 1C).…”

Section: Resultssupporting

confidence: 74%

Renal Fibrosis and Glomerulosclerosis in a New Mouse Model of Diabetic Nephropathy and Its Regression by Bone Morphogenic Protein-7 and Advanced Glycation End Product Inhibitors

et al. 2007

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“…in the STZ-diabetic rat [26][27][28][29][30]. In these studies the most pronounced upregulation was observed in the early stages of the disease.…”

Section: Discussionmentioning

confidence: 68%

Mannose-binding lectin deficiency attenuates renal changes in a streptozotocin-induced model of type 1 diabetes in mice

et al. 2007

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Aims/hypothesis An increasing amount of evidence indicates that mannose-binding lectin (MBL) plays a role in the development of diabetic nephropathy. The main objective of the study was to analyse whether MBL influences the effects of diabetes on the kidneys. Materials and methods In one group of wild-type mice and in one group of MBL double knockout mice we induced diabetes by the use of streptozotocin as a model of type 1 diabetes. Two groups of non-diabetic mice, wild-type and MBL knockout, were also included. By two-way ANOVA we evaluated if MBL modulated the effects of diabetes by testing the interaction between diabetes and MBL. Results MBL interacted with the effects of diabetes on three outcome measures: kidney weight (p<0.001), urinary albumin excretion (p=0.001) and the expression of collagen IVα1 (Col4a1) mRNA (p=0.002). This means that the effects that diabetes normally has on these parameters were significantly modified by MBL. MBL showed a tendency to interact with the effects of diabetes on glomerular basement membrane thickness and total mesangial volume (p=0.065 and p=0.063, respectively). Glomerular volume and total mesangial volume were significantly smaller in animals lacking MBL than in wild-type animals (p=0.006 and p=0.047, respectively). Conclusions/interpretation These findings, for the first time, show that the degree of kidney alteration as a consequence of diabetes is modified by MBL. These findings support a pivotal role of MBL in the development of diabetic kidney disease.

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“…Indeed, neonatal HP diet has been demonstrated to accelerate postnatal weight gain with mesenteric fat mass accretion, hypertriglyceridemia, hyperinsulinism, and resistance to leptin (20,27). These changes are known to increase SNGFR, to affect the glomerular endothelium barrier, to impair endothelium-dependent vasodilatation, and to stimulate the sympathetic nervous activity responsible for HT, one of the leading causes of CKD (28)(29)(30)(31)(32). Even though blood pressure was not monitored in the current study, we hypothesize that such metabolic, hormonal, and vascular changes enhanced the adaptive glomerular hemodynamic changes and renal injury already acquired during the neonatal period and accelerated the occurrence of proteinuria and glomerular sclerosis (33).…”

Section: Discussionmentioning

confidence: 99%

High protein intake in neonatal period induces glomerular hypertrophy and sclerosis in adulthood in rats born with IUGR

et al. 2015

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Background: Intrauterine growth restriction (IUGR) and postnatal nutrition are risk factors for cardiovascular and renal diseases in both humans and animals. The long-term renal effects of protein intake early in life remain unknown. The objective was to evaluate the effects of a neonatal feeding with high protein (HP) milk on renal functions and structure in IUGR male rats. Methods: Maternal gestational low protein diet was used to produce IUGR. At day 5, IUGR pups were gastrostomized in the "pup-in-the cup" model and received either normal protein (NP) milk or HP (+50% protein content) milk until day 21. After weaning, the animals were fed the same standard diet. Renal functions and structure were assessed at postnatal day 18 (D18) and in adult offspring. results: During the preweaning period, the postnatal weight gain between the two groups was unaffected. On D18, kidneys from HP offspring were heavier with significant glomerular hypertrophy (+40%, P < 0.05). HP diet was associated with significant proteinuria and glomerulosclerosis (+49%, P < 0.05). Glomerular number was unaltered. conclusion: Neonatal HP feeding following IUGR affects renal functions and structure at adulthood. These alterations may result from a single nephron glomerular hyperfiltration.

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Tumstatin Peptide, an Inhibitor of Angiogenesis, Prevents Glomerular Hypertrophy in the Early Stage of Diabetic Nephropathy

Cited by 168 publications

References 47 publications

Renal Fibrosis and Glomerulosclerosis in a New Mouse Model of Diabetic Nephropathy and Its Regression by Bone Morphogenic Protein-7 and Advanced Glycation End Product Inhibitors

Renal Fibrosis and Glomerulosclerosis in a New Mouse Model of Diabetic Nephropathy and Its Regression by Bone Morphogenic Protein-7 and Advanced Glycation End Product Inhibitors

Mannose-binding lectin deficiency attenuates renal changes in a streptozotocin-induced model of type 1 diabetes in mice

High protein intake in neonatal period induces glomerular hypertrophy and sclerosis in adulthood in rats born with IUGR

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