atrial-natriuretic-factor and Nephritis--Interstitial

Kidney injury molecule-1 (Kim-1) is associated with ischemic and proteinuric tubular injury; however, whether dysregulation of the renin-angiotensin system (RAS) can also induce Kim-1 is unknown. We studied Kim-1 expression in homozygous Ren2 rats, characterized by renal damage through excessive RAS activation. We also investigated whether antifibrotic treatment (RAS blockade or p38 MAP kinase inhibition) would affect Kim-1 expression. At 7 wk of age, homozygous Ren2 rats received a nonhypotensive dose of candesartan (0.05 mg x kg(-1) x day(-1) sc) or the p38 inhibitor SB-239063 (15 mg x kg(-1) x day(-1) sc) for 4 wk; untreated Ren2 and Sprague-Dawley (SD) rats served as controls. Kim-1 mRNA and protein expression were determined by quantitative PCR and immunohistochemistry, respectively, and related to markers of prefibrotic renal damage. Urinary Kim-1 was measured in 8-wk-old Ren2 and SD rats with and without angiotensin-converting enzyme inhibition (ramipril, 1 mg x kg(-1) x day(-1) in drinking water for 4 wk). Untreated Ren2 rats showed a >20-fold increase in renal Kim-1 mRNA (expressed as Kim-1-to-GAPDH ratio): 75.5 +/- 43.6 vs. 3.1 +/- 1.0 in SD rats (P < 0.01). Candesartan and SB-239063 strongly reduced Kim-1 mRNA: 3.1 +/- 1.5 (P < 0.01) and 9.8 +/- 4.2 (P < 0.05), respectively. Kim-1 protein expression in damaged tubules paralleled mRNA expression. Kim-1 expression correlated with renal osteopontin, alpha-smooth muscle actin, and collagen III expression and with tubulointerstitial fibrosis. Damaged tubular segments expressing activated p38 also expressed Kim-1. Urinary Kim-1 was increased in Ren2 vs. SD (458 +/- 70 vs. 27 +/- 2 pg/ml, P < 0.01) rats and abolished in Ren2 rats treated with ramipril (33 +/- 5 pg/ml, P < 0.01). Kim-1 is associated with development of RAS-mediated renal damage. Antifibrotic treatment through RAS blockade or p38 MAP kinase inhibition reduced Kim-1 in the homozygous Ren2 model.

Topics: Aldosterone; Angiotensin II Type 1 Receptor Blockers; Animals; Animals, Genetically Modified; Atrial Natriuretic Factor; Benzimidazoles; Biomarkers; Biphenyl Compounds; Blood Pressure; Cell Adhesion Molecules; Creatinine; Enzyme Inhibitors; Enzyme-Linked Immunosorbent Assay; Fibrosis; Immunohistochemistry; Male; Membrane Proteins; Nephritis, Interstitial; Osteopontin; p38 Mitogen-Activated Protein Kinases; Rats; Rats, Inbred Strains; Renin; Renin-Angiotensin System; Reverse Transcriptase Polymerase Chain Reaction; Tetrazoles

The present study was performed to explore the effect of exogenous infusions of atrial natriuretic peptide (ANP) on the early inflammatory response during acute sodium overload in normal rats.. Sprague Dawley rats were exposed to acute sodium overload (Na 1.5 M). Nonhypotensive doses of ANP (1 and 5 microg x kg(-1) x h(-1)) were infused simultaneously with sodium or after sodium infusion in order to evaluate prevention or reversion of the inflammatory response, respectively. We determined inflammation markers in renal tissue by immunohistochemistry.. Creatinine clearance was not reduced in any case. Sodium tubular reabsorption increased after sodium overload (334.3 +/- 18.7 vs. control 209.6 +/- 27.0 mEq x min(-1), p < 0.05) without changes in mean arterial pressure. This increase was prevented (228.9 +/- 26.4; p < 0.05) and reversed (231.5 +/- 13.9; p < 0.05) by ANP-5 microg x kg(-1) x h(-1). Sodium overload increased the expression of: RANTES (38.4.3 +/- 0.8 vs. 2.9 +/- 0.6%, p < 0.001), transforming-growth-factor-beta(1) (35.3 +/- 1.0 vs. 5.0 +/- 0.7%, p < 0.001), alpha-smooth muscle actin (15.6 +/- 0.7 vs. 3.1 +/- 0.3%, p < 0.001), NF-kappaB (9.4 +/- 1.3 to 2.2 +/- 0.5 cells/mm(2), p < 0.001), HIF-1alpha (38.2 +/- 1.7 to 8.4 +/- 0.8 cells/mm(2), p < 0.001) and angiotensin II (35.9 +/- 1.3 to 8.2 +/- 0.5%, p < 0.001). ANP-5 microg x kg(-1) x h(-1) prevented and reversed inflammation: RANTES (9.2 +/- 0.5 and 6.9 +/- 0.7, p < 0.001); transforming growth factor-beta(1) (13.2 +/- 0.7 and 10.2 +/- 0.5, p < 0.001) and alpha-smooth muscle actin (4.1 +/- 0.4 and 5.2 +/- 0.4, p < 0.001). Both prevention and reversion by ANP were associated with downregulation of NF-kappaB (3.2 +/- 0.4 and 2.8 +/- 0.5, p < 0.001) and angiotensin II (8.2 +/- 0.5 and 9.1 +/- 0.7, p < 0.001) and diminished hypoxia evaluated through HIF-1alpha expression (8.4 +/- 0.8 and 8.8 +/- 0.7, p < 0.001).. Our study provides evidence supporting a protective role of ANP in both prevention and reversion of renal inflammation in rats with acute sodium overload.

Topics: Angiotensin II; Animals; Atrial Natriuretic Factor; Hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit; Kidney Medulla; Kidney Tubules; Male; Nephritis, Interstitial; NF-kappa B; Rats; Rats, Sprague-Dawley; Saline Solution, Hypertonic; Sodium