#3078 MILD EXPERIMENTAL CKD IS ASSOCIATED WITH MYOCARDIAL FIBROSIS AND NOTCH/HEDGEHOG SIGNALING DYSREGULATION

Abstract

Abstract Background and Aims Chronic kidney disease (CKD) is an independent cardiovascular risk factor. The initial mechanisms of myocardial remodeling (MR) in CKD are poorly understood. The major developmental signaling pathways Notch, Hedgehog, Wnt, and Bmp seem to be involved in many crucial steps of MR (cardiomyocytes survival and regeneration, fibrotic response, angiogenesis), while their role in MR due to CKD was not previously studied. Phosphate (Pi) is essential for cellular signaling and its redistribution to the cardiovascular compartment in CKD could be a one of the mechanisms of MR. Here we investigated the involvement of Pi/PPi transport, and reactivation of developmental signaling pathways in myocardial alterations associated with mild CKD. Method We induce mild CKD by 3/4 nephrectomy in adult male SHRs (SHR-Nx, n=8) with normal phosphate intake (0.6%) and 2-month follow-up. Controls were sham-operated SHR (SHR-Sham, n=8) and Wistar Kyoto rats (WKY-Sham, n=8). We analyzed chronic kidney injury and Pi exchange parameters, serum intact parathyroid hormone (PTH), intact fibroblast growth factor 23 (FGF23), myocardial phosphorus content (ICP-AES), histomorphometry, PiT1 and PiT2 expression (IHC), and mRNA expression of Slc20a1, Slc20a2, Ankh, Mapk1, Mapk3, Bmp2, Bmp4, Ctnnb1, Fzd2, Sfrp2, Dkk1, Wif1, Numb, Notch1, Jag1, Hes1, Lgr4, Tnfrsf11b, Tnfsf11, Ptch1. Results Systolic blood pressure and myocardial mass index (MMI) were higher in SHRs vs WKY-Sham (Table 1). Decrease in creatinine clearance by 30% and an increase in albuminuria corresponded to mild CKD in SHR-Nx model (Table 1). In SHR-Nx, myocardial interstitial fibrosis was significantly higher (Figure 1), while MMI and cardiomyocyte diameter did not differ compared to SHR-Sham (Table 1). Myocardial alterations were accompanied by the increase in myocardium phosphorus content (Figure 1), down-regulation in PPi-exporter Ankh, and up-regulation in Hes1 and decline in Ptch1 mRNA expression (Figure 2). We found no changes in Slc20a1 and Slc20a2 mRNA levels (Figure 2). An appearance of PiT2-positive fibroblasts-like cells in myocardial interstitium was apparent in SHR-Nx rats (data not shown). Conclusion Myocardial alterations in mild CKD are manifested in an increase in its phosphorus content, interstitial fibrosis, and dysregulation in genes likely related to the induction of the myofibroblasts and extracellular matrix remodeling.