期刊
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE
卷 1864, 期 1, 页码 102-114出版社
ELSEVIER SCIENCE BV
DOI: 10.1016/j.bbadis.2017.10.005
关键词
Acute kidney injury (AKI); Matrix metalloproteinases (MMP); Fibrosis; Glomerular filtration; Sodium-transport
资金
- Carlos Chagas Filho Rio de Janeiro State Research Foundation (FAPERJ) [E-26/171.137/2006, E-26/111.665/2008]
- Brazilian National Research Council [303135/2015-8]
- Science Without Borders from CNPq-Brazil [420584/2013-7]
- National Institutes of Health-NIDDK [DK104375]
- CNPq
- FAPERJ
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [R01DK104375] Funding Source: NIH RePORTER
Renal ischemia-reperfusion injury (IRI) is a major cause of acute renal failure. Doxycycline (Dc) belongs to the tetracycline-class of antibiotics with demonstrated beneficial molecular effects in the brain and heart, mainly through matrix metalloproteinases inhibition (MMP). However, Dc protection of renal function has not been demonstrated. We determined whether low doses of Dc would prevent decreases in glomerular filtration rate (GFR) and maintain tubular Na+ handling in Wistar rats subjected to kidney I/R. Male Wistar rats underwent bilateral kidney ischemia for 30 min followed by 24 h reperfusion (I/R). Doxycycline (1, 3, and 10 mg/kg, i.p.) was administered 2 h before surgery. Untreated I/R rats showed a 250% increase in urine volume and proteinuria, a 60% reduction in GFR, accumulation of urea-nitrogen in the blood, and a 60% decrease in the fractional Na+ excretion due to unbalanced Na+ transporter activity. Treatment with Dc 3 mg/kg maintained control levels of urine volume, proteinuria, GFR, blood urea-nitrogen, fractional Na+ excretion, and equilibrated Na transporter activities. The Dc protection effects on renal function were associated with kidney structure preservation and prevention of TGF beta and fibronectin deposition. In vitro, total MMP activity was augmented in I/R and inhibited by 25 and 50 mu M Dc. In vivo, I/R augmented MMP-2 and -9 protein content without changing their activities. Doxycycline treatment downregulated total MMP activity and MMP-2 and -9 protein content. Our results suggest that treatment with low dose Dc protects from IRI, thereby preserving kidney function.
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