Klotho Gene Delivery Suppresses Endothelin‐1 Production but Upregulates ETB Receptors in Kidneys in SHR

Klotho is a newly‐discovered anti‐aging gene. We recently reported that klotho gene delivery prevents progression of spontaneous hypertension and renal damage in spontaneously hypertensive rats (SHRs). The purpose of this experiment was to further determine the effect of klotho gene delivery on the production of ET‐1 and regulation of SOD in kidneys of SHRs. AAV carrying mouse klotho full‐length cDNA (AAV.mKL) was constructed for in vivo expression of klotho. Four groups of male SHRs (5 rats/group) and 1 group of sex‐ and age‐matched WKY rats were used. Briefly, 4 groups of SHRs received IV injection of AAV.mKL, AAV.LacZ, AAV.GFP, and PBS, respectively. The WKY group received PBS and served as a control. AAV delivery of klotho gene significantly attenuated spontaneous hypertension. All animals were sacrificed at the end of week 12 after gene delivery. AAV.mKL decreased the ET‐1 levels in plasma and kidneys. Interestingly, klotho gene delivery increased ETB receptor expression in renal distal tubule and decreased the ETA/ETB receptor ratio, suggesting, for the first time, that klotho may up‐regulate renal ETB receptors. Klotho gene delivery also enhanced superoxide dismutase (SOD) expression in kidneys. Conclusions Klotho gene delivery suppressed the ET‐1 production and up‐regulated ETB and SOD in kidneys of SHRs. These findings may offer new insights into the relationship between renal klotho and the ET system in hypertension.