title: The role of Na+-H+ exchanger isoform 1 in aldosterone-induced glomerulosclerosis in vivo.
abstract: Aldosterone is reported to promote fibrosis of multiple organs. Recent studies showed that Na+-H+ exchanger isoform 1 (NHE1) was involved in mineralocorticoid-induced tissue fibrosis. The present study examined the role of NHE1 in aldosterone-induced glomerulosclerosis in rats. SD male rats were subjected to 5/6 nephrectomy and divided into four groups: rats subjected to sham operation were used as control (SHAM group), 5/6 nephrectomy (SNX group), SNX treated with aldosterone via osmotic mini-pump (ALDO group), and SNX treated with aldosterone plus NHE1 inhibitor 5-(N, N-Dimethyl) amiloride hydrochloride (DMA) (ALDO+DMA group). The rats were sacrificed at the 12th week. We found that aldosterone treatment significantly increased kidney weight/body weight ratio and systolic blood pressure compared with SNX rats. Aldosterone also increased proteinuria and serum creatinine level. The NHE1 antagonist DMA significantly reversed the effect of aldosterone on proteinuria, but had no effect on the aldosterone associated hypertension and the elevation of serum creatinine. The remnant kidney of 5/6 nephrectomized rats exhibited increased glomerulosclerosis score, tubulointerstitial fibrosis, and tubular proteinaceous cast, which were significantly enhanced by aldosterone treatment. DMA treatment significantly reduced aldosterone-associated glomerulosclerosis, but failed to improve aldosterone-induced tubulointerstitial fibrosis and tubular proteinaceous cast. The aldosterone-induced increase in renal TGFbeta1 and PCNA was significantly prevented by treatment with DMA. Our data showed that NHE1 inhibitor reduced aldosterone-induced glomerulosclerosis but not hypertension in 5/6 nephrectomized rats. The present study suggested that NHE1 contributed to aldosterone-induced-glomerulosclerosis and could be a potential therapeutic target for chronic kidney disease.
authors.affiliation: Department of Nephrology, Huashan Hospital, Institute of Nephrology, Fudan University, Shanghai, China.
authors.forename: Minmin
authors.initials: M
authors.lastname: Zhang
authors.forename: Jing
authors.initials: J
authors.lastname: Chen
authors.forename: Shaojun
authors.initials: S
authors.lastname: Liu
authors.forename: Li
authors.initials: L
authors.lastname: You
authors.forename: Shanyan
authors.initials: S
authors.lastname: Lin
authors.forename: Yong
authors.initials: Y
authors.lastname: Gu
mesh_terms: D000450:Aldosterone / Q000009:adverse effects* / Q000494:pharmacology; D000818:Animals; D027682:Cation Transport Proteins / Q000378:metabolism*; D005355:Fibrosis; D005921:Glomerulonephritis / Q000139:chemically induced* / Q000378:metabolism* / Q000503:physiopathology; D008297:Male; D009392:Nephrectomy; D051381:Rats; D017207:Rats, Sprague-Dawley; D012076:Renal Agents / Q000009:adverse effects* / Q000494:pharmacology; D000074082:Sodium-Hydrogen Exchanger 1; D017923:Sodium-Hydrogen Exchangers / Q000378:metabolism*
chemical_list: D027682:Cation Transport Proteins; D012076:Renal Agents; C490998:SLC9A1 protein, human; D000074082:Sodium-Hydrogen Exchanger 1; D017923:Sodium-Hydrogen Exchangers; D000450:Aldosterone