Doxycycline attenuates cisplatin-induced acute kidney injury through pleiotropic effects

Abstract

Cisplatin (CDDP) is a widely-used chemotherapeutic drug for solid tumors, but its nephrotoxicity is a major dose-limiting factor. Doxycycline (Dox) is a tetracycline antibiotic that has been commonly used in a variety of infections. Dox has been shown to possess several other properties, including anti-tumor, anti-inflammatory, anti-oxidative, and matrix metalloproteinase (MMP)-inhibiting actions. We therefore investigated whether Dox exerts renoprotective effects in CDDP-induced acute kidney injury (AKI). Twelve-week-old male C57BL/6J mice were divided into the following groups: 1) Control, 2) Dox (2 mg/ml in drinking water), 3) CDDP (25 mg/kg body weight, intraperitoneally), and 4) CDDP+Dox. After 7 days of pretreatment with Dox, CDDP was administered and the animals were sacrificed at day 1 or 3. We evaluated renal function along with renal histological damage, inflammation, oxidative stress, and apoptosis. MMP and serine protease activities in the kidney tissues were assessed using zymography. Administration of CDDP exhibited renal dysfunction and caused histological damage predominantly in the proximal tubules. Dox did not affect either expression of CDDP transporters or the accumulation of CDDP in renal tissues; however, it significantly ameliorated renal dysfunction and histological changes together with reduced detrimental responses such as oxidative stress and inflammation in the kidneys. Furthermore, Dox inhibited the activity of MMP-2 and MMP-9, as well as serine proteases in the kidney tissues. Finally, Dox markedly mitigated apoptosis in renal tubules. Thus, Dox ameliorated CDDP-induced AKI through its pleiotropic effects. Our results suggest that Dox may become a novel strategy for the prevention of CDDP-induced AKI in humans.

The Predictive Role of the Biomarker Kidney Molecule-1 (KIM-1) in Acute Kidney Injury (AKI) Cisplatin-Induced Nephrotoxicity

“…The latter are vital for both membrane structure maintenance and overall mitochondrial activity. As cisplatin levels increase, Bcl-2 is downregulated in response to p53 activation [87,88,89,90].…”

Recent Advances in Models, Mechanisms, Biomarkers, and Interventions in Cisplatin-Induced Acute Kidney Injury

“…Bcl family proteins are essential for maintenance of mitochondrial function and membrane integrity. There is a strong consensus that the anti-apoptotic mitochondrial protein, Bcl-2, is downregulated in response to cisplatin [40,44,70,75,76,78,79,83,84,88,89,104,105,106,107,108,109,110,111,112,113,114,115,116,117] through p53 activation [111,113,118]. One study, however, showed that Bcl-2 mRNA is increased after administration of cisplatin [119].…”

The Yin and Yang of Alarmins in Regulation of Acute Kidney Injury

“…Blocking of glycans with doxycycline, a broad-spectrum matrix metalloprotease inhibitor, was shown to restrict the secretion of pro-inflammatory cytokines in cisplatin and IRI-induced AKI ( 161 , 162 ). Heparanase inhibitors such as PG545 was found protective in experimental ischemic IRI ( 63 ) and is currently in clinical testing.…”