Pharmacological inhibition of galectin-3 protects against hypertensive nephropathy

Background: Galectin-3 activation is involved in the pathogenesis of renal damage and fibrogenesis. Limited data is available to suggest that galectin-3 targeted intervention is a potential therapeutic candidate for the prevention of chronic kidney disease (CKD). Methods: Homozygous TGR(mREN)27 (REN2) rats develop severe high blood pressure (BP) and hypertensive end-organ damage, including nephropathy and heart failure. Male REN2 rats were treated with the galectin-3 inhibitor N-acetyllactosamine (Gal3i) for 6 weeks; untreated REN2 and SD rats served as control. We measured cardiac function with echocardiogram and invasive hemodynamics before termination. BP and proteinuria were measured at baseline, three and six weeks. Plasma creatinine was determined at six weeks. Renal damage was assessed for focal glomerular sclerosis (FGS), glomerular desmin expression, glomerular and interstitial macrophages, kidney molecule-1 expression and alpha smooth muscle actin expression. Inflammatory cytokines and extracellular matrix proteinases were quantified by RT-qPCR. Results: Systolic BP was higher in REN2-con rats, with no effect of Gal3i treatment. Plasma creatinine and proteinuria were significantly increased in REN2-con rats; Gal3i treatment reduced both. Renal damage (FGS, desmin, interstitial macrophages, KIM-1, α-SMA, collagen I and III) was also improved by Gal3i. All inflammatory markers (CD68, IL-68, Galectin-3, MCP-1) were elevated in REN2-con rats and attenuated by Gal3i. Markers of extracellular matrix turnover were marginally altered in untreated REN2 rats compared with SD rats. Conclusion: Galectin-3 inhibition attenuated hypertensive nephropathy, as indicated by reduced proteinuria, improved renal function, and decreased renal damage. Drugs binding to galectin-3 may be therapeutic candidates for the prevention of CKD.