Klotho suppresses the renin-angiotensin system in adriamycin nephropathy.

Backgrounds: Klotho protein interacts with the transforming growth factor β (TGF-β) receptor and Wnt, which contribute to the progression of renal disease, inhibiting their signals. Renal and circulating klotho levels are diminished in chronic kidney disease.

Methods: Experiments were performed to assess whether supplementation of klotho protein could have protective effects on the kidney. Rats were injected with adriamycin (5 mg/kg) and divided into three groups: those treated with vehicle, those treated with klotho protein and those treated with klotho plus 4-benzyl-2-methyl-1,2,4-thiadiazolidine-3,5-dione (TDZD). Rats without adriamycin treatment were used as a control.

Results: Adriamycin reduced the serum klotho concentration and renal expression of klotho and E-cadherin. Adriamycin also increased the renal expression of Wnt, TGF-β, and angiotensinogen, as well as the renal abundance of β-catenin and angiotensin II. Klotho supplementation suppressed adriamycin-induced elevations of β-catenin and angiotensin II with sustained Wnt expression. Combined treatment with klotho and TDZD reversed the klotho-induced improvements in the renal abundance of β-catenin and angiotensin II as well as the expression of TGF-β and angiotensinogen without affecting E-cadherin.

Conclusions: Our data indicate that Wnt is involved in the pathogenesis of adriamycin nephropathy. Furthermore, klotho supplementation inhibited Wnt signaling, ameliorating renal angiotensin II. Finally, klotho protein appears to suppress epithelial-mesenchymal transition by inhibiting TGF-β and Wnt signaling.