Renal cortex neuronal nitric oxide synthase in response to rapamycin in kidney transplantation

Decreased renal neuronal nitric oxide synthase (nNOS) is present in various chronic kidney diseases although there is relative little known in chronic allograft nephropathy (CAN). Female sex increases the risk of acute rejection and calcineurin-inhibitor toxicity but decreases the risk of CAN. Rapamycin (RAPA) is an alternative immunosuppress although there is no information whether it is effective in females. We therefore investigated the efficacy of RAPA in both sexes and the impact of RAPA on renal cortex structure and nNOS expression. Male (M) and female (F) F344 kidneys were transplanted into same sex Lewis (ALLO) or F344 (ISO) recipients and treated with 1.6 mg/kg/day of RAPA for 10 days. Grafts were removed for renal histology and endothelial (e)NOS and neuronal (n)NOS protein measurements at 22 weeks. All ALLO rats survived without acute rejection. ALLO F survived with mild proteinuria and CAN at 22 weeks similar to ALLO M, while ISO F had better outcome than ISO M. Cortical nNOSα was undetectable in all RAPA groups; however, nNOSβ transcript and protein were compensatory increased. Both ALLO and ISO F showed higher medullary nNOSα but lower cortical eNOS abundance than M groups. In male ALLO RAPA decreased renal cortical nNOSα but increased nNOSβ expression. This may represent compensatory upregulation of nNOSβ when nNOSα-derived NO is deficient.