Upregulated Expression of Intestinal Antimicrobial Peptide HD5 Associated with Renal Function in IgA Nephropathy

Abstract

Purpose. It was reported that gut-kidney axis may play an important role in IgA nephropathy (IgAN). Previous five GWASs of different populations for IgAN have discovered several genes related to intestinal immunity, including DEFA gene. However, the roles of the encoded proteins of DEFA5/6 which were called intestinal antimicrobial peptides HD5 and HD6 were not clear in kidney disease, such as IgAN. The purpose of this study was to clarify the association of HD5 and HD6 with IgAN. Methods. We measured HD5 and HD6 in serum, urine, and kidney of IgAN patients and normal controls by ELISA, Western blot, and immunofluorescence. The association of HD5 or HD6 levels with clinical and pathologic phenotypes was analyzed. Results. Serum levels of HD5 and HD6 were significantly higher in IgAN patients than those in normal controls. Baseline serum HD5 levels were significantly associated with eGFR (P=0.002) and tubular atrophy/interstitial fibrosis (P=0.004) by stepwise multivariate regression analysis. Compared to the patients with serum HD5 below the median level, patients with elevated serum HD5 above the median level had a significantly worse renal outcome (log-rank test, P=0.009) by Kaplan-Meier analysis. A Cox regression model showed that serum HD5 was an independent prognostic factor (HR=1.239, P=0.029) after adjusting for the well-known predictors of outcome in IgAN patients. In renal biopsies of IgAN patients, HD5 was significantly expressed in the damaged proximal tubules, while no immunoreactive HD6 was found. Interestingly, the serum HD6 level of IgAN patients was significantly associated with gender. Conclusions. In IgAN patients, an elevated serum HD5 level at the time of renal biopsy was associated with poor renal outcomes. HD5 rather than HD6 was probably associated with renal function of IgAN patients.