Protection of Glomeruli from Hyperhomocysteinemia‐Induced Injury in Acid Sphingomyelinase Gene Knockout Mice

Abstract

Ceramide has been reported to initiate local oxidative injury in glomeruli under different pathological conditions. The present study was performed to explore the role of acid sphingomyelinase (ASM) in the development of hyperhomocysteinemia (hHcys)‐induced glomerular injury. Uninephrectomized ASM knockout (asm−/−) and wild type (asm+/+) mice were fed a folate free (FF) diet or normal chow for 8 weeks to produce hHcys. HPLC analysis revealed that plasma Hcys was significantly elevated in both asm−/− and asm+/+ mice. However, the plasma Hcys levels were significantly attenuated in asm−/−than inasm+/+ mice. FF diet significantly increased the renal ASM mRNA expression in asm+/+mice than in asm−/−mice. Morphological examinations showed that FF diet induced profound injury in glomeruli of asm+/+ mice which was markedly attenuated in asm−/− mice(the glomerular damage index (GDI) in asm+/+: 2.95± 0.09 vs. asm−/−: 1.51 ± 0.11). The decreased glomerular injury in asm−/− mice was accompanied by attenuated proteinuria associated with hHcy. Immunocytochemical analysis showed that FF diet decreased expression of podocin and nephrin, but increased desmin and ceramide levels in glomeruli of asm+/+ mice than in asm−/− mice. Electron spin resonance analysis demonstrated that FF diet significantly increased the NADPH‐dependent superoxide (O2·−) production in the kidneys of asm+/+ than in asm−/− mice. In conclusion, the observations reveal a pivotal role of ASM in the hHcy‐induced glomerular injury and ASM may be a therapeutic target for treatment or prevention of glomerulosclerosis associated with hHcys (supported by NIH grants HL‐091464, HL‐75316 and DK54927).