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Klotho Gene Deficiency Causes Hypertension and Kidney Damage
Author(s) -
BaileyDowns Lora,
Wang Xiuqing,
Sun Zhongjie
Publication year - 2011
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.25.1_supplement.661.13
Subject(s) - klotho , kidney , medicine , endocrinology
Hypothesis Klotho is a recently‐discovered anti‐aging gene. Genetic mutation of klotho results in multiple premature aging phenotypes and significantly shortens lifespan while overexpression of klotho extends lifespan. In humans, the klotho level declines with age while the prevalence of hypertension increases with age. The objective of this study was to test our hypothesis that knockdown of klotho gene leads to hypertension in rats. Methods & Results The in vivo RNAi knockdown of klotho was achieved by AAV delivery of klotho shRNA. In vivo expression of anti‐inflammatory cytokine IL‐10 was achieved by AAV delivery of human IL‐10 full‐length cDNA (IL10). KLshRNA significantly increased systolic and diastolic blood pressure. The KLshRNA‐induced hypertension may be mediated by inflammation because it can be abolished by expression of IL‐10. Indeed, KLshRNA caused inflammation as evidenced by increased IL‐6 expression and macrophage infiltration in kidneys. Notably, KLshRNA increased oxidative stress in kidneys as determined by significant increases in O 2 − and 4‐NHE levels (lipid peroxidation product). The KLshRNA‐induced oxidative stress may be due to downregulation of Mn‐SOD. KLshRNA caused glomerular collapses, a sign of severe kidney damage. IL‐10 gene delivery abolished KLshRNA‐induced oxidative stress and kidney damage. Both renal and circulating klotho levels were decreased by KLshRNA, indicating effective knockdown of klotho. Conclusion Klotho gene deficiency caused hypertension and kidney damage probably via inflammation and oxidative stress.