Site-1 protease-derived sPRR contributes to renal ischemia-reperfusion injury in mice by promoting macrophage classical activation.

Abstract

Soluble (pro) renin receptor (sPRR), the product of site-1 protease (S1P)-mediated cleavage of PRR, has emerged as an important player in the physiological and pathophysiological processes in the kidney. However, a potential role of S1P-derived sPRR in acute ischemia-reperfusion injury (IRI) still needs to be explored. Hence, the current study comprehensively examined the involvement of S1P-derived sPRR in the pathogenesis of renal IRI in mice. The mouse model of IRI was generated by inducing 30 min of bilateral ischemia, followed by reperfusion. Various parameters of renal injury were assessed at 24 h after acute kidney injury (AKI). The production of sPRR was blocked by pharmacological inhibition of S1P using PF-429242 or mutagenesis of the cleavage site of PRR (PRRR279V/L282V). The severity of AKI was estimated by plasma creatinine (Cr), blood urea nitrogen (BUN), urine microalbumin/Cr ratio, and tubular injury. Administration of PF-429242 significantly improved IRI-induced renal dysfunction, albuminuria, and tubular injury, accompanied by suppressed macrophage infiltration and M1 polarization. In parallel, IRI elevated plasma sPRR and urinary renin levels, which were both blunted by PF-429242 treatment. These findings were all recapitulated in PRRR279V/L282V mice. Together, these results suggest that S1P-derived sPRR plays a key role in the pathogenesis of renal IRI through macrophage M1 polarization.