Matrix Gla Protein Expression in Pericytes and Myofibroblasts Contributes to Renal Fibrosis

Renal fibrosis is the main pathologic change observed with the progression of chronic kidney disease (CKD), which predicts kidney outcomes. The ability to detect fibrosis early in the disease course may be crucial to identify those at the highest risk of CKD progression. Clinical studies have observed increased serum matrix Gla protein (MGP), a potent inhibitor of soft tissue calcification, in patients with CKD. In a cross-sectional study of patients with CKD, serum MGP levels were found to be associated with albuminuria and waist circumference after controlling for kidney function. To examine the impact of MGP on the progression of CKD, various mouse models were used in the current study. Using Cre-reporter, Rosa^Tomato;Mgp-Cre mice and a new knock-in model expressing hemagglutinin epitope-tagged MGP, it was identified that pericytes and myofibroblasts in healthy and folic acid (FA)-injured kidneys produce MGP. FA injection in Mgp^-/- mice induced significantly less renal fibrosis in comparison to the control mice because of a reduced number of pericytes and attenuated Notch signaling. In a complementary experiment, restoration of Mgp expression in myofibroblasts in Mgp^-/- mice leads to renal fibrosis as severe as in control mice. This work suggests that MGP expression in myofibroblasts exacerbates renal fibrosis in FA-injured kidneys.