Fosinopril and valsartan intervention in gene expression of Klotho, MMP-9, TIMP-1, and PAI-1 in the kidney of spontaneously hypertensive rats.
OBJECTIVE
To determine the role of fosinopril and valsartan intervention in Klotho, matrix metalloproteinase-9 (MMP-9), tissue inhibitor of metalloproteinase-1 (TIMP-1) and plasminogen activator inhibitor (PAI-1) gene expression in hypertensive renal interstitial fibrosis (RIF) in the kidney tissue of spontaneously hypertensive rats (SHR).


METHODS
We randomly divided 20 male 22-week-old SHR into 4 groups (5 in each group): a hypertension group (SHR group), a fosinopril group [Fos group, 10 mg/( kg · d) gavage], a valsartan group [Val group, 10 mg/( kg · d) gavage], and a fosinopril plus valsartan group [Fos + Val group, fosinopril 10 mg/( kg · d) + valsartan 50 mg/( kg · d) gavage]. Another five 22-week-old male Wistar Kyoto rats (WKY) were used as controls. Through monitoring the weight of the rats, tail artery pressure, 24-hour urine protein by fosinopril and/or valsartan intervention after the 8-week trial. RT-PCR and Western blot were used to detect the mRNA and protein expression of Klotho, MMP-9, TIMP-1, and PAI-1 in the kidneys.


RESULTS
RT-PCR showed that in the SHR group, Klotho mRNA and protein expression were significantly decreased(P<0.01), while mRNA and protein expression of MMP-9, TIMP-1, and PAI-1 were significantly higher compared with the WKY group(P<0.01). With fosinopril and / or valsartan intervention, Klotho mRNA expression in the Fos group (P<0.01), Fos + Val group (P<0.01), Val group (P<0.05), Klotho protein expression in the Fos group(P<0.05), Fos + Val group (P<0.05), Val group (P<0.01), were significantly increased compared with those in the SHR group. The mRNA and protein expression of MMP-9, TIMP-1, and PAI-1 in the Fos group, Val group, and Fos + Val group were significantly lower than those in the SHR group (P<0.01). The expression of Klotho mRNA had negative correlation with the expression of MMP-9 mRNA (r= -0.864, P<0.01), TIMP-1 mRNA (r=-0.725, P<0.01) and PAI-1 mRNA (r=-0.785, P<0.01). The Klotho protein expression had negative correlation with the expression of MMP-9 protein (r=-0.614, P<0.05), TIMP-1 protein (r=-0.579, P<0.05), and PAI-1 protein (r=-0.552, P<0.05).


CONCLUSIONS
Anti-aging gene Klotho and the genes related with extracellular matrix degradation gene MMP-9, TIMP-1, PAI-1 are involved in hypertensive renal injury. The expression of Klotho and MMP-9, TIMP-1, and PAI-1 is closely correlated. Fosinopril and valsartan which increase the Klotho mRNA and protein expression can alter the expression of Klotho-MMPs/TIMPs, which may be the main mechanism to prevent interstitial fibrosis.
Department of Nephrology, Xiangya Hospital, Central South University, Changsha 410008, China. cxm6131@yahoo.com.cn
Xiaomiao
X
Cheng
Qiaoling
Q
Zhou
Shudian
S
Lin
Rong
R
Wu
D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D005355:Fibrosis / Q000517:prevention & control; D017328:Fosinopril / Q000494:pharmacology*; D005966:Glucuronidase / Q000235:genetics / Q000378:metabolism*; D006973:Hypertension / Q000235:genetics* / Q000378:metabolism; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D000090265:Klotho Proteins; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism*; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011897:Random Allocation; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D013777:Tetrazoles / Q000494:pharmacology*; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000235:genetics / Q000378:metabolism; D014633:Valine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000068756:Valsartan
D000959:Antihypertensive Agents; D017395:Plasminogen Activator Inhibitor 1; D012333:RNA, Messenger; D013777:Tetrazoles; D019715:Tissue Inhibitor of Metalloproteinase-1; D000068756:Valsartan; D005966:Glucuronidase; D000090265:Klotho Proteins; D020780:Matrix Metalloproteinase 9; D014633:Valine; D017328:Fosinopril