Mild Chronic Kidney Disease Associated with Low Bone Formation and Decrease in Phosphate Transporters and Signaling Pathways Gene Expression

Abstract

The initial phases of molecular and cellular maladaptive bone responses in early chronic kidney disease (CKD) remain mostly unknown. We induced mild CKD in spontaneously hypertensive rats (SHR) by either causing arterial hypertension lasting six months (sham-operated rats, SO6) or in its’ combination with 3/4 nephrectomy lasting two and six months (Nx2 and Nx6, respectively). Sham-operated SHRs (SO2) and Wistar Kyoto rats (WKY2) with a two-month follow-up served as controls. Animals were fed standard chow containing 0.6% phosphate. Upon follow-up completion in each animal, we measured creatinine clearance, urine albumin-to-creatinine ratio, renal interstitial fibrosis, inorganic phosphate (Pi) exchange, intact parathyroid hormone (PTH), fibroblast growth factor 23 (FGF23), Klotho, Dickkopf-1, sclerostin, and assessed bone response by static histomorphometry and gene expression profiles. The mild CKD groups had no increase in renal Pi excretion, FGF23, or PTH levels. Serum Pi, Dickkopf-1, and sclerostin were higher in Nx6. A decrease in trabecular bone area and osteocyte number was obvious in SO6. Nx2 and Nx6 had additionally lower osteoblast numbers. The decline in eroded perimeter, a resorption index, was only apparent in Nx6. Significant downregulation of genes related to Pi transport, MAPK, WNT, and BMP signaling accompanied histological alterations in Nx2 and Nx6. We found an association between mild CKD and histological and molecular features suggesting lower bone turnover, which occurred at normal levels of systemic Pi-regulating factors.

piRNAs and miRNAs Can Bind to mRNA of <i>KLOTHO</i> and <i>FGF23</i> Genes

“…The importance of their biological role is undoubted. The FGF23 gene is a member of a large family of fibroblast growth factors [94], which is most associated with the KLOTHO gene in anti-aging processes [95]. A number of publications have examined the relationship of FGF23 and KLOTHO genes in physiological processes and in various diseases [96][97][98][99][100][101][102][103][104].…”

N1F(Improved-Nephropathy 1 Formula) ameliorates renal interstitial fibrosis via inhibiting extracellular matrix deposition and regulating the FGF23/P38MAPK/Wnt pathway

“…In addition, it has been found that MAPK signaling activation can inhibit Wnt signaling by up-regulating DKK1 protein. Consequently, Klotho, an upstream protein, acts as a co-receptor protein for FGF23, forming the FGF23-klotho complex, which can serve to activate the MAPK signaling pathway and exert biological effects [18][19] [20].…”