Dysregulation of bone and myocardial inorganic phosphate transporters and downstream cell signals in early-stage mild chronic kidney disease-mineral and bone disorder: An experimental study

Chronic kidney disease–mineral and bone disorder (CKD-MBD) significantly contributes to cardiovascular morbidity and mortality in CKD patients, raising questions about the molecular mechanisms linking cardiac and bone abnormalities. In this study, adult male spontaneously hypertensive rats (SHRs) underwent 3/4 nephrectomy (Nx) to induce mild CKD-MBD, with sham-operated SHRs (SO) serving as controls. All animals were fed a standard diet containing 0.6 % phosphorus.

Exhibiting renal dysfunction comparable to human CKD stage 2, Nx rats had higher levels of serum inorganic phosphate (Pi), calciprotein particles (CPPs), and myocardial phosphorus (P) without differences in serum PTH, FGF23, kidney and bone P content. Compared to controls, the experimental group showed features of lower bone turnover with reduced osteoblast and osteocyte numbers and decreased eroded perimeter, alongside myocardial hypertrophy and fibrosis. In bone and myocardium, reciprocal alterations of a tissue expression of Pi-transporters and MAPK-signals were found. Reduced bone turnover associated with a lower tissue expression of Slc20a1 (PiT1) and osteogenic Mapk1 (ERK2). In myocardium, Slc20a2 (PiT2) and phospho-ERK1/2 expression were upregulated at gene and protein levels in Nx rats versus controls.

These findings suggest that, in the setting of CKD-associated Pi retention, maladaptive bone and myocardial responses are mediated by the dysregulation of Pi transporters and down-stream ERK1/2 signals.