nephrin and goralatide

Diabetic nephropathy is the main cause of end-stage renal disease. N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP), a physiological tetrapeptide hydrolyzed by the angiotensin-converting enzyme (ACE), has antifibrotic effects in the cardiovascular system and in the kidney in experimental models of hypertension, heart failure and renal disease. The aim of the study was to evaluate the effect of Ac-SDKP in diabetic nephropathy and the potential additive effect of Ac-SDKP, when compared to ACE inhibitors alone, on the development of renal fibrosis.. Diabetes was induced in 28 Sprague-Dawley rats by a single intraperitoneal injection of streptozotocin. Control rats (n = 10) received only buffer solution. An ACE inhibitor (ramipril, 3 mg/kg/day) was administered to 11 diabetic rats. After 2 months, Ac-SDKP (1 mg/kg/day) was administered by osmotic minipumps for 8 weeks to 7 diabetic rats and to 6 diabetic rats treated with ramipril. Osmotic minipumps delivered saline solution in the corresponding sham-treated rats (diabetic rats, n = 10, and ramipril-treated diabetic rats, n = 5).. Diabetic rats showed a significant increase in blood glucose level, urinary albumin excretion and renal fibrosis, and a reduction of glomerular nephrin expression with respect to control rats. Ac-SDKP administration significantly reduced renal fibrosis in diabetic rats, without significantly reducing urinary albumin excretion. Ramipril treatment caused a significant decrease in albuminuria and renal fibrosis and restored glomerular nephrin expression. Administration of Ac-SDKP, in addition to ramipril, further reduced renal fibrosis with respect to ramipril alone, while it did not improve the antiproteinuric effect of ramipril.. Ac-SDKP administration reduces renal fibrosis in diabetic nephropathy. Addition of Ac-SDKP to ACE inhibition therapy improves the reduction of renal fibrosis with respect to ACE inhibition alone, suggesting a beneficial effect of this pharmacological association in diabetic nephropathy.

Topics: Albuminuria; Angiotensin-Converting Enzyme Inhibitors; Animals; Diabetic Nephropathies; Drug Evaluation, Preclinical; Glomerular Filtration Rate; Growth Inhibitors; Kidney Glomerulus; Male; Membrane Proteins; Nephrosclerosis; Oligopeptides; Ramipril; Rats; Rats, Sprague-Dawley

Hypertension-induced renal injury is characterized by inflammation, fibrosis and proteinuria. Previous studies have demonstrated that N-acetyl-Ser-Asp-Lys-Pro (Ac-SDKP) inhibits renal damage following diabetes mellitus and antiglomerular basement membrane nephritis. However, its effects on low-renin hypertensive nephropathy are not known. Thus, we hypothesized that Ac-SDKP has renal protective effects on deoxycorticosterone acetate (DOCA)-salt hypertensive mice, decreasing inflammatory cell infiltration, matrix deposition and albuminuria.. We uninephrectomized 16-week-old C57BL/6J mice and treated them with either placebo, DCOA (10 mg/10 g body weight subcutaneous) and 1% sodium chloride with 0.2% potassium chloride in drinking water (DOCA-salt) or DOCA-salt with Ac-SDKP (800 μg/kg per day) for 12 weeks. We measured blood pressure, urine albumin, glomerular matrix, renal collagen content, monocyte/macrophage infiltration and glomerular nephrin expression.. Treatment with DOCA-salt significantly increased blood pressure (P < 0.01), which remained unaltered by Ac-SDKP. Ac-SDKP decreased DOCA-salt-induced renal collagen deposition, glomerular matrix expansion and monocyte/macrophage infiltration. Moreover, DOCA-salt-induced increase in albuminuria was normalized by Ac-SDKP (controls, 10.8 ± 1.7; DOCA-salt, 41 ± 5; DOCA-salt + Ac-SDKP, 13 ± 3 μg/10 g body weight per 24 h; P < 0.001, DOCA-salt vs. DOCA-salt + Ac-SDKP). Loss of nephrin reportedly causes excess urinary protein excretion; therefore, we determined whether Ac-SDKP inhibits proteinuria by restoring nephrin expression in the glomerulus of hypertensive mice. DOCA-salt significantly downregulated glomerular nephrin expression (controls, 37 ± 8; DOCA-salt, 10 ± 1.5% of glomerular area; P < 0.01), which was partially reversed by Ac-SDKP (23 ± 4.0% of glomerular area; P = 0.065, DOCA-salt vs. DOCA-salt + Ac-SDKP).. We concluded that Ac-SDKP prevents hypertension-induced inflammatory cell infiltration, collagen deposition, nephrin downregulation and albuminuria, which could lead to renoprotection in hypertensive mice.

Topics: Albuminuria; Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Collagen; Desoxycorticosterone; Hypertension, Renal; Kidney; Macrophages; Male; Membrane Proteins; Mice; Mice, Inbred C57BL; Oligopeptides; Sodium Chloride, Dietary