Effect of Periostin on Renal Fibrosis and Renal Function Deterioration

Abstract

Background: Periostin is a matricellular protein and plays a vital role in tissue regeneration, fibrosis, and wound healing via its interaction with integrin. Recently, the role of periostin has been explored in the field of nephrology. We investigated the role of periostin, the effect of periostin blockade in renal fibrogenesis, and its clinical significance including renal histologic findings and prognosis in IgA nephropathy (IgAN). Methods: We investigated the function of periostin in vivo in wild-type and periostin-deficient mice (POSTN-KO) in a unilateral ureteral obstruction (UUO) model. For the in vitro experiments, primary cultured inner medullary collecting duct (IMCD) cells from the wild-type and POSTN-KO mice were used. For an experiment involving human, serum and urine periostin were measured in 314 IgA nephropathy patients using ELISA. The patients were divided into 3 groups by urine periostin/creatinine (uPOSTN/Cr): group 1 (undetectable), group 2 (lower than the median), and group 3 (higher than the median). Results: Periostin expression was strongly induced by the UUO in the wild-type mice. In vitro, the administration of recombinant TGF-β increased periostin expression in the wild-type IMCD cells. The effect of periostin blockade was examined by three ways. Compared to the wild-type mice, the POSTN-KO mice showed a more preserved kidney structure and less fibrous tissues. Fibrosis-related genes and the mRNA expression levels of inflammatory cytokines were increased in the wild-type mice and were significantly decreased in the POSTN-KO mice. The integrin blockade peptide and anti-periostin polyclonal antibody decreased the fibrosis-related gene expression. The uPOSTN/Cr level was correlated with pathologic classifications and both initial and final IDMS-MDRD eGFRs (P<0.001). Histologically, group 3 patients were correlated with severe interstitial fibrosis/tubular atrophy (P=0.004), interstitial inflammation (P=0.007), hyaline arteriolosclerosis (P=0.001), and glomerular sclerosis (P<0.001). A higher initial uPOSTN/Cr level was associated with a greater decline in eGFR during follow-up (P=0.043 when initial eGFR ≥ 60

P=0.025 when eGFR < 60 mL/min/1.73 m2), and the renal outcomes with ESRD (P=0.003), ESRD and/or eGFR decrease of > 30% (P=0.033), and ESRD and/or eGFR decrease of > 50% (P=0.046) occurred significantly more in group 3. In multivariate analysis, uPOSTN group 3 (HR, 2.839

CI, 1.013-7.957

P=0.047) was independently associated with ESRD in IgAN patients. Conclusion: Periostin is one of the markers of renal fibrosis and may augment the progression of fibrogenesis as an extracellular matrix protein. Periostin blockade attenuated renal fibrogenesis via inhibiting the TGF-β signaling pathway, inflammation, and apoptosis. Urine POSTN/Cr value at initial diagnosis correlated with renal fibrosis and predicted the renal outcomes in patients with IgAN. Thus, periostin could be a promising urinary biomarker for renal fibrosis and periostin inhibition may be a therapeutic target for the amelioration of renal disease progression.