Brain natriuretic peptide mitigates TIMP2 induction and reinstates extracellular matrix catabolic activity GSK3β inhibition in glomerular podocytes exposed to a profibrogenic milieu.

Brain natriuretic peptide (BNP) has a demonstrable anti-fibrotic effect on diverse organ systems, including the kidney. To understand the molecular mechanism underlying this renoprotective effect, the efficacy of BNP was examined in an model of glomerular sclerosis by exposing glomerular podocytes to transforming growth factor (TGF)β1-containing media that recapitulates the profibrogenic milieu in chronic glomerular disease. BNP mitigates extracellular matrix (ECM) accumulation in TGFβ1-treated podocytes, as evidenced by Sirius red assay and staining, concomitant with a restoration of the ECM catabolizing activity, as assessed by pulse chase analysis. This effect was in parallel with a mitigating effect on TGFβ1-elicited overexpression of tissue inhibitor of metalloproteinases (TIMP)2, a key inhibitor of a multitude of ECM-degrading metalloproteinases. Mechanistically, glycogen synthase kinase (GSK)3β, a key player in pathogenesis of podocyte injury and glomerulopathies, seems to be involved. BNP treatment considerably induced GSK3β inhibition, marked by inhibitory phosphorylation at the serine 9 residue, and this significantly correlated with the abrogated TIMP2 induction in TGFβ1-injured podocytes. Moreover, genetic knockout of GSK3β in podocytes is sufficient to attenuate the TGFβ1 induced TIMP2 expression and ECM deposition, reminiscent of the effect of BNP. Conversely, ectopic expression of a nonphosphorylatable GSK3β mutant abolished the inhibitory effect of BNP on TGFβ1-elicited TIMP2 overexpression and ECM accumulation, signifying an essential role of GSK3β inhibition in mediating the effect of BNP. Collectively, BNP possesses an anti-fibrotic activity in glomerular epithelial cells. This finding, if validated , may open a new avenue to the treatment of glomerulosclerosis.