Activated protein C alters inflammation and protects renal function in sepsis

Activated protein C (aPC) confers survival benefit in patients with sepsis, yet its protective mechanism(s) remain unclear. Herein, we determined time-dependent severity of renal dysfunction during polymicrobial sepsis. We hypothesized aPC restores renal function by preserving organ architecture and reducing inflammation.

Sprague-Dawley rats underwent sham operation or cecal ligation and puncture (CLP). At 6 or 24 h post-surgery, kidney function was assessed by plasma electrolytes, blood urea nitrogen (BUN), and creatinine levels. Renal architecture was examined histologically. In the next series of experiments, 24-h post-surgery, animals were treated with vehicle or aPC (1 mg/kg) for 4 d, and kidney function and circulating cytokine levels were measured. Plasma was collected and assayed for BUN, creatinine, and lactate dehydrogenase (LDH) levels. Serum cytokine levels were measured by ELISA.

Plasma electrolytes, BUN, creatinine, and renal architecture were altered 6 h after CLP. Treatment with aPC significantly inhibited sepsis-induced elevations in BUN, creatinine, LDH levels, and improved renal architecture. After CLP, interferon gamma (INFγ) decreased, while interleukins-1beta and -10 (IL-1β and IL-10) increased; these effects were attenuated by aPC treatment.

Our data demonstrate that renal dysfunction occurs as early as 6 h following sepsis and continues thereafter. Treatment with aPC attenuated INFγ and IL-1β changes, and preserved renal function in sepsis. These data suggest aPC may confer a survival advantage by reducing systemic inflammation and, in doing so, preserving organ function.