3 years ago

FL-926-16, a novel bioavailable carnosinase-resistant carnosine derivative, prevents onset and stops progression of diabetic nephropathy in db/db mice

Carlo M Pesce, Giancarlo Aldini, Annunziata Lapolla, Claudia Blasetti Fantauzzi, Giuseppe Pugliese, Marica Orioli, Carla Iacobini, Enrica Salomone, Andrea Giaccari, Stefano Menini
Background and Purpose The advanced glycation endproducts (AGEs) participate in the pathogenesis of diabetic nephropathy (DN) by promoting renal inflammation and injury. L-carnosine acts as a quencher of the AGE precursors reactive carbonyl species (RCS), but it is rapidly inactivated by carnosinase. This study evaluated the effect of FL-926-16, a carnosinase-resistant and bioavailable carnosine derivative, on the onset and progression of DN in db/db mice. Experimental Approach Adult male db/db mice and coeval db/m controls were left untreated or treated with FL-926-16 (30 mg·kg-1 body weight) from week 6 to 20 (prevention protocol) or from week 20 to 34 (regression protocol). Key Results In the prevention protocol, FL-926-16 significantly attenuated increases in creatinine (-80%), albuminuria (-77%), proteinuria (-75%), mean glomerular area (-34%), fractional (-40%) and mean (-42%) mesangial area in db/db mice. This protective effect was associated with reduction of glomerular matrix protein expression and cell apoptosis, circulating and tissue oxidative and carbonyl stress, and renal inflammatory markers, including the NLRP3 inflammasome. In the regression protocol, progression of DN was completely blocked, though it was not reversed by FL-926-16. In cultured mesangial cells, FL-926-16 prevented NLRP3 expression induced by RCS, but not by the AGE Nε-carboxymethyllysine. Conclusion and Implications These data show that FL-926-16 is effective in preventing the onset and halting progression of DN in db/db mice by quenching RCS, thereby reducing the accumulation of their protein adducts and the consequent inflammatory response. In a future perspective, this novel compound may represent a promising AGE-reducing approach for DN therapy.

Publisher URL: http://onlinelibrary.wiley.com/resolve/doi

DOI: 10.1111/bph.14070

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