Early glycosilation products induce glomerular hyperfiltration in normal rats

Sabbatini, Massimo; G, Sansone; Uccello, F.; Giliberti, A.; Conte, Giuseppe; Andreucci, Vittorio E.

doi:10.1038/ki.1992.363

Cited by 75 publications

(34 citation statements)

References 23 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…This effect is opposite to that seen after an infusion of glycated albumin (47) and more consistent with changes seen in advanced disease or with severe hyperglycemia (48). Notably, both of these states are associated with high levels of circulating AGE.…”

Section: Discussioncontrasting

confidence: 46%

Interactions between Renin Angiotensin System and Advanced Glycation in the Kidney

Thomas

Tikellis²,

Burns³

et al. 2005

Journal of the American Society of Nephrology

131

View full text Add to dashboard Cite

Although hemodynamic and metabolic factors are individually implicated in the development of diabetic nephropathy, their interaction has not been defined clearly. In this study, the effects of angiotensin II (Ang II) and advanced glycation end products (AGE) both individually on each other are explored and compared. In the first study arm, Sprague-Dawley rats received a continuous infusion of AGE-modified rat serum albumin (RSA) or unmodified RSA for 4 wk with or without the angiotensin receptor type 1 antagonist valsartan. In the second arm, animals received a continuous infusion of Ang II (58.3 ng/kg per min) with or without the AGE inhibitor pyridoxamine. Components of the intrarenal renin-angiotensin system were measured using real time reverse transcription-PCR, immunohistochemistry, and standard angiotensin-converting enzyme (ACE) activity assays. Renal and serum AGE were quantified by immunohistochemistry, ELISA, and AGE-fluorescence. After an infusion of AGE-RSA, renal expression of angiotensinogen, ACE, renin, and angiotensin receptor type 1 were increased significantly (all P < 0.01), and ACE activity was elevated. This was associated with tubular and glomerular hypertrophy and AGE accumulation, which could be antagonized by valsartan. However, valsartan had no effect on increased filtration fraction associated with an AGE-RSA infusion. At the same time, an infusion of Ang II increased the serum and renal accumulation of AGE and advanced oxidation protein products and induced renal hypertrophy and salt retention that could be antagonized by pyridoxamine. However, pyridoxamine had no effect on renal vasoconstriction manifested by reduced renal blood flow. AGE and Ang II have overlapping activities in the kidney. The beneficial effects of blockade of either pathway underline the importance of this interaction in diabetic renal disease and the aging kidney.

show abstract

Section: Discussioncontrasting

confidence: 46%

Interactions between Renin Angiotensin System and Advanced Glycation in the Kidney

Thomas

Tikellis²,

Burns³

et al. 2005

Journal of the American Society of Nephrology

131

View full text Add to dashboard Cite

show abstract

“…It is not likely that the effects of these agents on GFR can be explained by differences in glycaemic control because none of the treatments influenced plasma glucose, body weight or glycated haemoglobin. Other investigators have reported that early glycation products induce glomerular hyperfiltration [21] but it was difficult to determine how accurately early AGEs had been separated from late AGEs in this study. This indicates that direct effects of AGEs on glomerular filtration cannot be excluded.…”

Section: Discussionmentioning

confidence: 57%

Renoprotective effects of a novel inhibitor of advanced glycation

et al. 2001

View full text Add to dashboard Cite

It has been hypothesized that the biochemical process of advanced glycation plays an important part in the pathogenesis of diabetic vascular complications [1] and particularly in diabetic nephropathy [2]. This hypothesis was based primarily on the renoprotective effects observed with aminoguanidine (AG), an inhibitor of advanced glycation end-product formation (AGE) [3]. Aminoguanidine, however, has other actions including inhibiting nitric oxide synthase, and thus, nitric oxide production [4]. Nitric oxide has direct effects on renal haemodynamics in diabetes [5,6] and therefore it has been difficult to ascertain if the benefits of aminoguanidine relate primarily to inhibiting renal AGE accumulation.We compared the effect of AG in diabetic rats with ALT-946, N-(2-Acetamidoethyl) hydrozinecarboximidamide hydrochloride, a more potent inhibitor of AGE-derived protein modification than AG. ALT-946 is also a poor inhibitor of nitric oxide synthase with fewer toxic side effects than AG (unpublished results). We have reported previously that AG Diabetologia (2001) AbstractAims/hypothesis. ALT-946, an inhibitor of advanced glycation with a minimal inhibitory effect on nitric oxide synthase, was compared with aminoguanidine in experimental diabetic nephropathy. Methods. In vitro and in vivo assays were used to assess the ability of ALT-946 to inhibit AGE-protein cross-link formation. Diabetic animals were randomly allocated into groups receiving aminoguanidine for 32 weeks, ALT-946 or vehicle (untreated). As a delayed intervention protocol, an additional diabetic group was treated with ALT-946 from week 16 to week 32 of the study. Non-diabetic rats were studied concurrently. Systolic blood pressure, body weight, plasma glucose, glycated haemoglobin and urinary albumin excretion were measured serially. Accumulation of advanced-glycation end products in the kidney was assessed by immunohistochemistry.Results. The ALT-946 inhibitor was more potent than aminoguanidine in inhibiting AGE-protein crosslinking both in vitro and in vivo. Increased albuminuria observed in diabetic rats was attenuated in all three treatment groups. We found no difference in body weight, blood pressure or glycaemic control with any of the treatments. The untreated diabetic group had a twofold increase in glomerular staining for advanced-glycation end products compared with the diabetic groups which received treatment. Conclusion/interpretation. ALT-946 is a potent inhibitor of advanced renal glycation end-product accumulation and reproduces the renoprotective effects of aminoguanidine. Therefore, ALT-946 should be considered as a treatment for preventing or retarding diabetic nephropathy. [Diabetologia (2001) 44: 108± 114]

show abstract

“…For quantitation, sections were coded and read by an observer unaware of the experimental protocol applied. [10][11][12][13][14][15] glomeruli were selected at random in PAS-stained sections from each animal in each experimental group. The extent of increase in mesangial matrix was determined by the presence of PAS-positive material in the mesangial region using a digital planimeter (Southern Microscope Instruments, Inc., Atlanta, GA) and factored by the glomerular tuft area.…”

Section: Methodsmentioning

confidence: 99%

“…This postulate has been strengthened with experimental evidence demonstrating that glycated serum proteins adversely affect renal glomerular capillary function, structure, and metabolism (10)(11)(12)(13). In previous studies, we have shown that human sera containing diabetic concentrations of glycated albumin inhibit the replication of murine mesangial cells in culture and stimulate the production and gene expression of type IV collagen, the principal constituent of the expanded extracellular matrix observed in the diabetic renal glomerulus (14)(15)(16)(17)(18).…”

Section: Introductionmentioning

confidence: 99%

Prevention of diabetic nephropathy in db/db mice with glycated albumin antagonists. A novel treatment strategy.

Cohen¹,

Sharma²,

Ying³

et al. 1995

J. Clin. Invest.

144

View full text Add to dashboard Cite

Accelerated protein glycation in diabetes has been mechanistically linked to the pathogenesis of diabetic nephropathy. Because glycated albumin induces abnormalities in cultured mesangial cells that resemble those characterizing the glomerular mesangium in diabetes, and monoclonal antibodies (A717) specific for Amadori-modified glycated albumin prevent these abnormalities, we postulated that in vivo administration of A717 could retard the progression of diabetic nephropathy. To test this hypothesis, diabetic db/db mice and their nondiabetic db/m littermates were treated with eight consecutive weekly injections of 150 jig of A717 (Fab fragments) to reduce the elevated plasma glycated albumin concentration, or with irrelevant murine IgG (MIg). Relative to nondiabetics, diabetic mice (MIg treated) manifested proteinuria (3.35±0.15 vs 0.87±0.1 mg albumin/mg creatinine), 3.8-fold increase in mesangial matrix fraction, and renal cortical overexpression of mRNAs encoding al (IV) collagen (2.6-fold increase) and fibronectin (3.8-fold increase). Treatment of db/db mice with A717 significantly reduced the proteinuria (1.52±0.3 mg/mg creatinine), inhibited mesangial matrix expansion, and attenuated overexpression of matrix mRNAs. The nephropathic protective effects of A717 were independent of any change in blood glucose concentrations. Antibodies unreactive with glycated albumin did not duplicate the beneficial effects of A717. Thus, abrogating the biologic effects of increased glycated albumin with A717 has a salutary influence on the pathogenesis of diabetic nephropathy and has novel therapeutic potential in its management. (J. Clin. Invest. 1995Invest. . 95:2338Invest. -2345

show abstract

Early glycosilation products induce glomerular hyperfiltration in normal rats

Cited by 75 publications

References 23 publications

Interactions between Renin Angiotensin System and Advanced Glycation in the Kidney

Interactions between Renin Angiotensin System and Advanced Glycation in the Kidney

Renoprotective effects of a novel inhibitor of advanced glycation

Prevention of diabetic nephropathy in db/db mice with glycated albumin antagonists. A novel treatment strategy.

Contact Info

Product

Resources

About