Abstract 428: N-Acetyl-Ser-Asp-Lys-Pro (Ac-SDKP) Exerts Renal Protective Effects in DOCA-salt-hypertensive Mice
Background and hypothesis: Hypertension-induced renal injury is characterized by inflammation, fibrosis and proteinuria, which are prevented by angiotensin converting enzyme (ACE) inhibitors. Although ACE inhibitors substantially increase plasma levels of N-acetyl-Ser-Asp-Lys-Pro (Ac-SDKP), effects of Ac-SDKP on hypertensive nephropathy is not known. We hypothesized that Ac-SDKP exerts renal protective effects in hypertensive mice by inhibiting inflammatory cell infiltration, collagen deposition and albuminuria.
Study design and results: We uninephrectomized 16-week old wild type (WT) mice and treated them with 1. Placebo, 2. Deoxycorticosterone acetate (30mg/mouse subcutaneous) and 1% NaCl +0.2% KCl in drinking water (DOCA-salt) and 3. DOCA-salt +Ac-SDKP (800 μg/Kg/day) for 12 weeks. We measured blood pressure, urine albumin, renal collagen content, monocyte/macrophage infiltration and glomerular nephrin expression. Treatment of mice with DOCA-salt significantly increased blood pressure, which was unaltered by Ac-SDKP (controls, 106 ±2; DOCA, 142 ±5.1; DOCA +Ac-SDKP, 144 ±6.4 mmHg; P <0.05, control vs. DOCA). Ac-SDKP decreased DOCA-salt-induced renal collagen deposition (μg collagen/mg dry kidney- controls, 7.6 ±1.5; DOCA, 15.5 ±1.1; DOCA +Ac-SDKP, 9.9 ±1.2; P <0.05, DOCA vs. DOCA +Ac-SDKP) and monocyte/macrophage infiltration (controls, 62 ±17; DOCA, 246±39; DOCA +Ac-SDKP, 70 ±8/mm2; P <0.05, DOCA vs. DOCA +Ac-SDKP) in these mice. Similarly, DOCA salt-induced increase in albuminuria was normalized by Ac-SDKP (controls, 10.8 ±1.7; DOCA,41±5; DOCA +Ac-SDKP, 13 ±3 μg/10gmBW/24hr; P<0.01, DOCA vs. DOCA +Ac-SDKP).In search of the mechanism by which Ac-SDKP could inhibit proteinuria, we measured glomerular slit pore protein, nephrin, lack of which causes congenital nephrotic syndrome of Finnish type. DOCA salt significantly downregulated glomerular nephrin expression (controls,37 ±8; DOCA, 10 ±1.5 % staining/glomerulus; P <0.01), which was partially reversed by Ac-SDKP (23 ±4.0; P<05 vs. DOCA).
Conclusion: We conclude that Ac-SDKP prevents inflammatory cell infiltration, collagen deposition, decrease in nephrin expression and albuminuria, which could lead to renoprotection in hypertensive mice.