Indoxyl Sulfate Reduces Klotho Expression and Promotes Senescence in the Kidneys of Hypertensive Rats

Background: Administration of indoxyl sulfate, a uremic toxin, promotes progression of chronic kidney disease in rats affected by the disease. Klotho, an anti-aging gene, is expressed in the kidneys, and its renal expression is decreased in chronic kidney disease. This study aimed to clarify whether indoxyl sulfate could reduce klotho expression and contribute to cell senescence in the kidneys of hypertensive rats. Methods: The rats used for this study were segregated in to the following 4 groups: (1) Dahl salt-resistant normotensive rats (DN), (2) Dahl salt-resistant normotensive indoxyl sulfate-administered rats (DN 1 IS), (3) Dahl salt-sensitive hypertensive rats (DH), and (4) Dahl salt-sensitive hypertensive indoxyl sulfate-administered rats (DH 1 IS). After 32 weeks, their kidneys were excised for histological and immunohistochemical analysis for klotho, senescence-associated beta-galactosidase, p16(INK4a), p21(WAF1/CIP1), p53, and retinoblastoma protein (Rb). Results: DH 1 IS rats showed decreased expression of klotho, increased expression of senescence-associated beta-galactosidase, p16(INK4a), p21(WAF1/CIP1), p53, and Rb in renal tubular cells, and increased tubulointerstitial fibrosis and mesangial expansion as compared with DH rats. Further, DN 1 IS rats showed decreased expression of klotho as compared with DN rats. Conclusion: Administration of indoxyl sulfate to hypertensive rats reduced renal expression of klotho and promoted cell senescence with expression of senescence-related proteins, such as p16(INK4a), p21(WAF1/CIP1), p53, and Rb, which was accompanied by renal fibrosis. (C) 2011 by the National Kidney Foundation, Inc. All rights reserved.