15 research outputs found
Suramin: a potential therapy for diabetic nephropathy.
OBJECTIVE: To 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 METHODS: Groups 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. RESULTS: Immunoblot 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. CONCLUSIONS: Delayed 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
Urinary ATP Synthase Subunit β Is a Novel Biomarker of Renal Mitochondrial Dysfunction in Acute Kidney Injury
Effect of delayed administration of suramin on renal leukocyte infiltration in 9/17 week db/db mice.
<p>Mice were treated as described in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0073655#pone-0073655-g001" target="_blank">Figure 1</a>. Representative photomicrographs of neutrophil and monocyte staining assessed by formation of stable pinkish-red colored (arrows) complex of free naphthol and diazonium salts following incubation of kidney sections from 9/17 week non-diabetic and diabetic mice ± suramin intervention, respectively. All fields were chosen from the cortical regions of the kidney sections. Original magnification, 200 X. <b>A</b>. Quantitative analysis of renal leukocyte infiltration assessed by number of pink colored dots in a total of 25 fields in the cortical region of kidney sections. Data are expressed as mean ± SE (n = 4). <b>*</b> Significantly different from respective non-diabetic <i>db/m</i> mice (<i>p</i>≤0.05). @ Significantly different from vehicle-treated 9 week diabetic <i>db/db</i> mice (<i>p</i>≤0.05).</p
Effect of delayed administration of suramin on deposition of renal fibrogenic material COL1A2 in 9/17 week db/db mice.
<p>Mice were treated as described in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0073655#pone-0073655-g001" target="_blank">Figure 1</a>. Representative photomicrographs of COL1A2 deposition in kidney sections from 9/17 week non-diabetic and diabetic mice ± suramin intervention, respectively. All fields were chosen from the cortical regions of the kidney sections. Original magnification, 200 X. <b>A</b>. Quantitative analysis of renal COL1A2 assessed by brown staining in the epithelial cells lining the proximal tubules (arrows) in a total of 25 fields in the cortical region of kidney sections. Data are expressed as mean ± SE (n = 4). * Significantly different from respective non-diabetic <i>db/m</i> mice (<i>p</i>≤0.05). # Significantly different from vehicle-treated diabetic <i>db/db</i> mice (<i>p</i>≤0.05). @ Significantly different from vehicle-treated 9 week diabetic <i>db/db</i> mice (<i>p</i>≤0.05).</p
Effect of delayed administration of suramin on urinary protein excretion and creatinine clearance (CrCl) in 9/17 week db/db mice.
<p>Mice were treated as described in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0073655#pone-0073655-g001" target="_blank">Figure 1</a>. Urine was collected on ice 24 h before euthanization and (<b>A</b>) Urinary protein excretion normalized to urinary creatinine; (<b>B</b>) Creatinine clearance; in 9 and 17 week non-diabetic and diabetic mice ± suramin intervention, respectively, were measured. Data are expressed as mean ± SE (n = 3–6). * Significantly different from suramin-treated diabetic <i>db/db</i> mice. (<i>p</i>≤0.05).</p
Effect of delayed administration of suramin on body weights and serum glucose levels in 9/17 week db/db mice.
<p>Non-diabetic <i>db/m</i> heterozygous mice of 8/16 weeks and diabetic <i>db/db</i> homozygous mice of 8/16 weeks, respectively, were treated with either saline vehicle or 10 mg suramin/kg (i.v., dissolved in saline). Mice in all groups were terminated a week later. (<b>A</b>) Body weights; and (<b>B</b>) Serum glucose levels; in 9 and 17 week non-diabetic and diabetic mice ± suramin intervention, respectively, were measured. Data are expressed as mean ± SE (n = 6–10). <b>*</b> Significantly different from respective non-diabetic <i>db/m</i> mice. (<i>p</i>≤0.05). <b>#</b> Significantly different from 9 week diabetic <i>db/db</i> mice. (<i>p</i>≤0.05).</p
Effect of delayed administration of suramin on renal pro-fibrotic markers in 9/17 week db/db mice.
<p>Mice were treated as described in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0073655#pone-0073655-g001" target="_blank">Figure 1</a>. Representative Western blots showing profibrotic markers: Renal TGF-β<sub>1</sub>, renal phospho-Smad-3 and α-SMA in kidneys of 9/17 week <i>db/db</i> mice ± suramin intervention. (<b>A</b>) Densitometric analysis of renal TGF-β<sub>1</sub>; (<b>B</b>) Renal phospho-Smad-3; and (<b>C</b>) Renal α-SMA. Data were normalized by GAPDH which served as internal control. Data are expressed as mean ± SE (n = 4). <b>*</b> Significantly different from respective non-diabetic <i>db/m</i> mice (<i>p</i>≤0.05). # Significantly different from vehicle-treated diabetic <i>db/db</i> mice (<i>p</i>≤0.05). @ Significantly different from vehicle-treated 9 week diabetic <i>db/db</i> mice (<i>p</i>≤0.05).</p