Genetic deficiency of anti-aging gene klotho exacerbates early nephropathy in STZ-induced diabetes in male mice.
Klotho is a recently discovered anti-aging gene and is primarily expressed in kidneys. In humans, the klotho level decreases with age whereas the prevalence of chronic kidney disease (CKD) increases with age. Diabetic nephropathy is the most common form of CKD, which leads to end-stage renal disease. A decrease in klotho has been found in kidneys of patients with diabetic nephropathy. The purpose of this study is to assess whether klotho gene deficiency affects early diabetic nephropathy in a mouse of model of type 1 diabetes induced by streptozotocin (STZ). Male KL(+/-) mutant and wild-type mice (6-8 weeks) were injected with multiple low doses of STZ. Renal functions and renal blood flow were assessed. Kidneys were collected for histological examination and molecular assays of TGFβ1 and mammalian targets of rapamycin (mTOR) signaling. Klotho deficiency in KL(+/-) mutant mice exacerbated STZ-induced increases in urine albumin, blood urea nitrogen, expansion of mesangial matrix in renal glomeruli, and kidney hypertrophy, suggesting a protective role of klotho in kidney function and structure. Klotho deficiency did not affect renal blood flow. Notably, klotho deficiency significantly increased phosphorylation of Smad2, indicating enhanced TGFβ1 signaling in kidneys. Klotho deficiency also increased phosphorylation of mTOR and S6 (a downstream effector of mTOR), indicating enhanced mTOR signaling in kidneys of early diabetic mice. Thus, klotho gene deficiency may make kidneys more susceptible to diabetic injury. Klotho gene deficiency exacerbated early diabetic nephropathy via enhancing both TGFβ1 and mTOR signaling in kidneys.
MD, PhD, FAHA, Professor of Physiology, Director, The Robert and Mary Cade Laboratory, BMSB 662A, Box 26901, Department of Physiology, College of Medicine, University of Oklahoma Health Sciences Center, 940 S. L. Young Boulevard, Oklahoma City, OK 73126-0901. Zhongjie-sun@ouhsc.edu.
Yi
Y
Lin
Makoto
M
Kuro-o
Zhongjie
Z
Sun
D000818:Animals; D003922:Diabetes Mellitus, Type 1 / Q000150:complications*; D003928:Diabetic Nephropathies / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D004198:Disease Susceptibility; D005966:Glucuronidase / Q000235:genetics / Q000378:metabolism*; D006579:Heterozygote; D006984:Hypertrophy; D007668:Kidney / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D000090265:Klotho Proteins; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008817:Mice, Mutant Strains; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D051437:Renal Insufficiency / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D038601:Ribosomal Protein S6 / Q000378:metabolism; D015398:Signal Transduction; D051899:Smad2 Protein; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000378:metabolism
D038601:Ribosomal Protein S6; D051899:Smad2 Protein; C497783:Smad2 protein, mouse; C508961:Tgfb1 protein, mouse; D053773:Transforming Growth Factor beta1; C448579:ribosomal protein S6, mouse; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; D005966:Glucuronidase; D000090265:Klotho Proteins