Diabetes-Induced Renal Injury in Rats Is Attenuated by Suramin

Korrapati, Midhun C.; Shaner, Brooke E.; Neely, Benjamin A.; Alge, Joseph L.; Arthur, John M.; Schnellmann, Rick G.

doi:10.1124/jpet.112.196964

Cited by 25 publications

(20 citation statements)

References 59 publications

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“…Hyperglycemia-induced activation of proinflammatory mediators like NF-κB is part of the pathogenesis of DN [7], [16], [17], [18], [19]. The active and proinflammatory form of NF-κB, phosphorylated-p65, increased in both 9 and 17 week old db/db mice when compared to 9 and 17 week old db/m mice ± suramin (Fig.…”

Section: Resultsmentioning

confidence: 91%

Suramin: A Potential Therapy for Diabetic Nephropathy

et al. 2013

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ObjectiveTo determine whether delayed administration of a single dose of suramin, a drug that has been used extensively in humans to treat trypanosomiasis, attenuates renal injury in a leptin receptor deficient C57BLKS/J db/db type 2 diabetic nephropathy (T2DN) mouse model.Research Design and MethodsGroups of female non-diabetic (control) db/m and diabetic db/db mice of 8 and 16 weeks of age, respectively, were treated with suramin (10 mg/kg) or saline i.v. All animals were euthanized one week later. Measurements in mice 1 week following treatment included the following: body weight; blood glucose; urinary protein excretion; pathological lesions in glomeruli and proximal tubules; changes in protein expression of pro-inflammatory transcription factor nuclear factor κB (NF-κB) and intracellular adhesion molecule-1 (ICAM-1), profibrotic transforming growth factor-β1 (TGF-β1), phospho-SMAD-3 and alpha-smooth muscle actin (α-SMA); and immunohistochemical analysis of leukocyte infiltration and collagen 1A2 (COL1A2) deposition.ResultsImmunoblot analysis revealed increased NF-κB, ICAM-1, TGF-β1, phospho-SMAD-3, and α-SMA proteins in both 9 and 17 week db/db mice as compared to db/m control mice. Immunohistochemical analysis revealed moderate leukocyte infiltration and collagen 1A2 (COL1A2) deposition in 9 week db/db mice that was increased in the 17 week db/db mice. Importantly, suramin significantly decreased expression of all these markers in 9 week db/db mice and partially decreased in 17 week db/db mice without altering body weight, blood glucose or urinary protein excretion. There was no difference in creatinine clearance between 9 week db/m and db/db mice ± suramin. Importantly, in the 17 week db/db mice suramin intervention reversed the impaired creatinine clearance and overt histological damage.ConclusionsDelayed administration of a single dose of suramin in a model of T2DN attenuated inflammation and fibrosis as well as improved renal function, supporting the use of suramin in T2DN.

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Section: Resultsmentioning

confidence: 91%

Suramin: A Potential Therapy for Diabetic Nephropathy

et al. 2013

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“…Furthermore, COL1A2 is associated with tubulointerstitial fibrosis (25). In this study, the levels of renal MCP-1 and COL1A2 mRNA expression increased with age in THM.…”

Section: Discussionmentioning

confidence: 63%

Effects of aging and uninephrectomy on renal changes in Tsukuba hypertensive mice

Inui¹,

Mochida²,

Yamairi

et al. 2013

Biomedical Reports

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Abstract. Renal dysfunction is accelerated by various factors such as hypertension, aging and diabetes. Glomerular hyperfiltration, considered one of the major risk factors leading to diabetic nephropathy, is often encountered in diabetic patients. However, the interrelationship of these risk factors during the course and development of renal dysfunction has not been fully elucidated. In this study, the effects of aging and uninephrectomy (UNx)-induced hyperfiltration on renal changes were investigated in Tsukuba hypertensive mice (THM) carrying both human renin and angiotensinogen genes. In THM, the urinary albumin/creatinine (Alb/Cr) ratio was elevated with age without a concomitant increase in the plasma Cr concentration. Moreover, the urinary neutrophil gelatinase-associated lipocalin/Cr (NGAL/Cr) ratio, the renal monocyte chemoattractant protein-1 (MCP-1) mRNA expression and the renal collagen type I α 2 (COL1A2) mRNA expression were also increased with age. Age-related albuminuria in THM is likely caused by renal tubular damage, enhanced inflammatory response and tubulointerstitial fibrosis. Furthermore, following UNx, the urinary Alb̸Cr ratio and the plasma Cr concentration were increased in THM. The urinary NGAL/Cr ratio and the renal MCP-1 and COL1A2 mRNA expression were not affected by UNx. These results suggested that UNx-induced albuminuria in THM was caused by glomerular dysfunction, rather than renal tubular injury. In conclusion, this study demonstrated for the first time the effects of aging and UNx on renal changes in THM. These findings strongly reinforce the significance of applying a diversity of therapeutic approaches to the management of renal dysfunction. IntroductionChronic kidney disease (CKD) is a major public health concern worldwide because of the increasing prevalence of end-stage renal failure requiring dialysis or kidney transplantation and the increased risk of morbidity and mortality due to cardiovascular diseases (1-6). Aging leads to renal structural changes and functional decline. Imai et al (7) and Coresh et al (8) suggested that the prevalence of CKD increases with age. Moreover, a significantly higher prevalence of CKD was reported in hypertensive patients compared to normotensive subjects (8,9). High systemic blood pressure leads to pressure elevation in the glomerular capillaries, which is associated with renal vascular dysfunction. Elevated pressure in the glomerular capillaries results in glomerular sclerosis, increased albuminuria and decreased glomerular filtration rate (10). Furthermore, glomerular hyperfiltration is often observed during the early stages of diabetes and may contribute to the development of diabetic nephropathy (11,12). Thus, the progression of CKD is affected by various risk factors such as aging, hypertension and hyperfiltration. However, the interrelationship of individual risk factors during the course of renal dysfunction has not been fully elucidated.Tsukuba hypertensive mice (THM) are transgenic mice carrying both human renin and angiotensino...

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“…In this case, they clearly demonstrated that liquid chromatographytandem mass spectroscopy-based analysis revealed increases in urinary proteins that are early indicators of DN (e.g., cystatin C and peroxiredoxin-1) in the STZ group, which were blocked by suramin. 41 In conclusion, we focus on renal tissue sample but not urine sample. This is the reason why the opposite trend in Prdx1 expression between renal tissue and urine.…”

Section: Discussionmentioning

confidence: 99%

Potential biomarkers associated with diabetic glomerulopathy through proteomics

Hsu

Lei

et al. 2015

Renal Failure

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Diabetic nephropathy (DN) is characterized by the development of progressive glomerulosclerotic lesions gradually leading to an increasing loss of functioning kidney parenchyma. Relatively little proteomic research of isolated glomeruli of experimental animal models has been done so far. Isolated glomerular proteomics is an innovative tool that potentially detects simultaneous expressions of glomeruli in diabetic pathological contexts. We compared the isolated glomerular profiles of rats with and without diabetes. The proteins in the aliquots of glomeruli were subjected to two-dimensional gel electrophoresis. The protein spots were matched and quantified using an imaging analysis system. The peptide mass fingerprints were identified by matrix-assisted laser desorption ionization time-of-flight mass spectrometry and a bioinformation search. We found that diabetes increased collagen type I and collagen type IV levels in diabetic glomeruli when compared to normal control group using Dynabeads. We found that rats with diabetes had significantly higher abundance of the Protein disulfide isomerase associated 3, Aspartoacylase-3,3-hydroxymethyl-3-methylglutaryl-Coenzyme A lyase, Lactamase beta 2 and Agmat protein. However, diabetic glomeruli in rats had significantly lower levels of the Regucalcin, rCG52140, Aldo-keto reductase family 1, Peroxiredoxin 1, and L-arginine: glycine amidinotransferase. These proteins of interest were reported to modulate disturbances in the homeostasis of endoplasmic reticulum stress, disturbance of inflammatory and fibrinogenic activities, impairing endothelial function, and dysregulation in the antioxidation capacity/oxidative stress in several tissue types under pathological contexts. Taken together, our high-throughput isolated glomerular proteomic findings indicated that multiple pathological reactions presumably occurred in DN.

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Diabetes-Induced Renal Injury in Rats Is Attenuated by Suramin

Cited by 25 publications

References 59 publications

Suramin: A Potential Therapy for Diabetic Nephropathy

Suramin: A Potential Therapy for Diabetic Nephropathy

Effects of aging and uninephrectomy on renal changes in Tsukuba hypertensive mice

Potential biomarkers associated with diabetic glomerulopathy through proteomics

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