PB1053 - Protective role of the SerpinE2 PN-1 in renal disease

Background: Renal fibrosis is regarded as the final common pathway in chronic kidney diseases. In glomerulonephritis (GN), fibrin formation and deposition are also observed within the kidney, and glomerular intracapillar microthrombosis frequently occurs. SerpinE2, also known as PN-1, is a tissue-retained protease inhibitor of the serpin family known to be antithrombotic, that has anti-fibrotic effects and to be directly involved in inflammatory processes.

Aims: To analyze PN-1 expression in kidney and decipher its role in GN development.

Methods: GN was induced in PN-1-/- and wild-type littermate (WT) mice by nephrotoxic serum (NTS) injections (n = 5). Leucocyte infiltration was studied on kidney sections by CD45 labelling. PN-1 and inflammatory markers expression were analyzed by RT-PCR on renal cDNA and coagulation markers were analyzed by western blot on kidney lysates or renal-tissue conditioned media.

Results: NTS administration increased protein and mRNA PN-1 expression levels and this increase was correlated to the progression of GN (r2 = 0.9311).
Interestingly, the progression of GN was accelerated in mice lacking expression of PN-1, as evidenced by the aggravated histological features and worsened renal function. Moreover, the kidneys of these mice exhibited increased fibrin deposition, leucocyte infiltration and fibrinogen levels compared to WT.
Consistently, mRNA expression of inflammatory markers like IL6, TNFalpha or MCP-1 was higher in PN-1-/- compared to WT mice (2.7, 3.2 and 7.7 fold, respectively). Similarly, mRNAs of pro-fibrotic markers like TGFbeta and collagens I and III were also increased in PN-1-/- kidneys (2.2, 3.2 and 2.7 fold, respectively). In addition, the levels of fibrin(ogen) degradation products and of thrombin were increased in conditioned media from kidneys of PN-1-/- compared to WT mice.

Conclusion(s): Altogether, these results suggest that PN-1 plays a protective role in renal disease by limiting fibrin deposition and restraining inflammatory reaction.