MO415: Kidney Expression of Canonical WNT Inhibitors and Β-Catenin in Experimental Models of Arterial Hypertension and Nephrectomy Induced CKD

Abstract

Abstract BACKGROUND AND AIMS The canonical Wnt (cWnt) is known to be involved in tubular recovery after kidney injury and fibrosis, while arterial hypertension (AH) promotes cWnt activity. The aim of the study was to investigate the kidney expression of β-catenin and cWnt inhibitors in AH and chronic kidney disease (CKD) models. METHOD AH-CKD was performed by 3/4 nephrectomy (NE) in spontaneously hypertensive rats (SHR) with 2 or 6 months of experimental exposure (Table). Sham-operated (SO) SHRs and Wistar Kyoto rats (WKY) served as controls, and 6 mo exposure SO-SHRs were used as AH-induced CKD. Serum creatinine (Cr), renal sclerostin (Sost) and dickkopf-1 (Dkk1) gene expression were measured. The following parameters of kidney morphology were analyzed and calculated quantitatively: the areas of tubular dystrophy (TD) (PAS), renal fibrosis (RF) (Masson's trichrome), β-catenin (BC), sclerostin (SOST) and dickkopf-1 (DKK1) IHC-staining. RESULTS The experimental models were corresponded to early (SO6, NE2) and mild (NE6) CKD (Table). In all groups, BC membrane IHC staining in epithelial cells and nuclear expression in podocytes were determined, SOST and DKK1 cytoplasmic IHC staining in tubular epithelium were detected (Figure). The tubular and interstitial lesions in NE (Table) were accompanied by cytoplasmic BC localization in epithelial and interstitial cells (Figure) with a decrease in dickkopf-1 gene (Table) and protein (Figure) expression, increase in Sost gene expression and SOST IHC staining of tubular intracellular vesicles (Figure). Long-term exposure to hypertension (SO6) resulted in the renal function decline and RF comparable to NE2 (Table), while TD and levels of Wnt inhibitors and BC IHC staining area did not differ significantly vs SO2, WKY (Table). In the pooled analysis, the RF directly correlated with the BC renal expression (r = 0.76, P = 0.005) and negatively with Dkk1 expression (r = −0.45, P = 0.028); the TD negatively correlated with Sost expression (r = −0.80, P = 0.002). CONCLUSION Tubular and interstitial damage in NE and AH-induced CKD is associated with BC up-regulation. The decrease in dickkopf1 and BC cytoplasmic accumulation may be required for renal fibrosis. The sclerostin expression is likely to be essential for the pathogenesis of TD.