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Renal fibrosis is the main pathological 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 expression of serum matrix Gla protein (MGP), a potent inhibitor of soft tissue calcification, in CKD patients. In a cross-sectional study of CKD patients, we found that serum MGP levels were associated with albuminuria and waist circumference after controlling for kidney function which modified the association between MGP and albuminuria. To examine the impact of MGP on the onset and 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 in healthy kidneys and myofibroblasts in the folic acid (FA)-injured kidneys are the primary sources of MGP production. FA injection in Mgp -/- mice induced significantly less renal fibrosis in comparison to the control mice due to 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 control mice. This work suggests that MGP expression in myofibroblasts exacerbates renal fibrosis in FA-injured kidneys.
Bak et al. (Tue,) studied this question.