Project 7: Therapeutic implications and pathophysiological role of calprotectin in acute kidney injury
We identified in the first funding period urinary calprotectin (S100A8/S100A9) as a new diagnostic marker for acute kidney injury (AKI). It differentiates between prerenal and intrinsic AKI. Several biomarkers have been identified in AKI so far, but none of them has improved patient’s outcome. Consequently, no candidate biomarker has proceeded to daily clinical practice. Here, we examine whether calprotectin, as a diagnostic tool, leads to an improvement of patient’s outcome. To this end, a clinical study assesses urinary calprotectin concentration prior to contrast media (CM) exposition in patients without overt renal disease. In the first study period, calprotecin was measured without therapeutic consequences. In the second study period, those patients with increased calprotectin concentrations prior to the application of contrast media will receive nephroprotective strategies (saline infusion). The occurrence of contrast induced AKI (CI-AKI) will be the primary endpoint. Moreover, a pathophysiological role of calprotectin in AKI will be investigated in a rodent model of AKI (ischemia/reperfusion injury, I/RI). Calprotectin is a mediator protein of the innate immune system. Preliminary data from our collaborators indicate that calprotectin may have beneficial effects in the regenerative response after AKI. S100A8/S100A9 can exert antiinflammatory effects via the protease activated receptor-2 (PAR2). PAR2 is highly expressed in the kidney and – in addition to its role in inflammation – is known to mediate vasodilation (see unifying hypothesis). We test anti-inflammatory and vasodilatory effects of calprotectin in AKI by the use of S100A9 -/- mice. The hemodynamic effects of calprotectin will be examined in the isolated mouse kidney and in vasa recta. With regard to the upstream regulation of calprotectin in AKI, we have performed a microarray analysis of NF-κB deficient vs. wildtype mice after I/RI indicating an NF-κB dependent expression of calprotectin. A regulation of calprotectin by NF-κB signaling has already been described in hepatocytes. Thus, we put forward a regulatory role of NF-κB on calprotectin, which is relevant for the long-term outcome of AKI. To test a regulatory role of NF-κB, we will investigate tubular injury and regeneration after I/RI in S100A9 -/- and tubular specific NF-κB deficient mice.