Antifibrotic, nephroprotective effects of paricalcitol versus calcitriol on top of ACE-inhibitor therapy in the COL4A3 knockout mouse model for progressive renal fibrosis

Background. The COL4A3−/− mouse serves as animal model for progressive renal fibrosis. Using this animal model, the present study investigates the nephroprotective effects of Paricalcitol versus Calcitriol alone and on top of ACE-inhibitor therapy. Methods. Eighty six mice were divided into six groups: (PC) with Paricalcitol 0.1 mcg/kg, (CA) Calcitriol 0.03 mcg/kg (dose equipotent), (PLAC) vehicle 0.1 mL i.p. five times per week, (ACE + PC) Paricalcitol plus Ramipril, (ACE + CA) Calcitriol plus Ramipril and (ACE + PLAC) vehicle plus Ramipril 10 mg/kg/day p.o. ACE therapy started pre-emptively in Week 4, PC/CA therapy was initiated in 6-week-old animals with ongoing renal fibrosis and lasted for 8 weeks. Four to six animals were sacrificed after 9.5 weeks and kidneys were further investigated using histological, immunohistological and Westernblot techniques. Survival until end-stage renal failure was determined in the remaining animals. Results. PC, but not CA, prolonged lifespan until renal failure by 13% compared with untreated controls (P = 0.069). ACEinhibition prolonged lifespan by >50%. Added on top of ACE inhibition, ACE + PC (but not ACE + CA) even further prolonged lifespan by additional 18.0% (P < 0.01 versus ACE + PLAC) and improved renal function (blood urea nitrogen; P < 0.05 versus ACE + CA). Accumulation of extracellular matrix and renal scarring was decreased in PC and ACE + PCtreated mice. Conclusions. The present study demonstrated a substantial nephroprotective and antifibrotic effect of the vitamin D-receptor activator Paricalcitol on top of early ACE inhibition in the COL4A3−/− model of progressive kidney fibrosis. The synergistic effect of Paricalcitol on top of RAAS-blockade might as well be valuable in other chronic kidney diseases.