title: Recombinant α-Klotho may be prophylactic and therapeutic for acute to chronic kidney disease progression and uremic cardiomyopathy.
abstract: α-Klotho is highly expressed in the kidney, and its extracellular domain is cleaved and released into the circulation. Chronic kidney disease (CKD) is a state of α-Klotho deficiency, which exerts multiple negative systemic effects on numerous organs including the cardiovascular system. Since acute kidney injury (AKI) greatly escalates the risk of CKD development, we explored the effect of α-Klotho on prevention and treatment on post-AKI to CKD progression and cardiovascular disease. Therein, ischemia reperfusion injury-induced AKI was followed by early administration of recombinant α-Klotho or vehicle starting one day and continued for four days after kidney injury (CKD prevention protocol). A CKD model was generated by unilateral nephrectomy plus contralateral ischemia reperfusion injury. Late administration of α-Klotho in this model was started four weeks after injury and sustained for 12 weeks (CKD treatment protocol). The prevention protocol precluded AKI to CKD progression and protected the heart from cardiac remodeling in the post-AKI model. One important effect of exogenous α-Klotho therapy was the restoration of endogenous α-Klotho levels long after the cessation of exogenous α-Klotho therapy. The treatment protocol still effectively improved renal function and attenuated cardiac remodeling in CKD, although these parameters did not completely return to normal. In addition, α-Klotho administration also attenuated high phosphate diet-induced renal and cardiac fibrosis, and improved renal and cardiac function in the absence of pre-existing renal disease. Thus, recombinant α-Klotho protein is safe and efficacious, and might be a promising prophylactic or therapeutic option for prevention or retardation of AKI-to-CKD progression and uremic cardiomyopathy.
authors.affiliation: Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA; Charles and Jane Pak Center for Mineral Metabolism and Clinical Research, University of Texas Southwestern Medical Center, Dallas, Texas, USA. Electronic address: ming-chang.hu@utsoutwestern.edu.
authors.forename: Ming Chang
authors.initials: MC
authors.lastname: Hu
authors.affiliation: Charles and Jane Pak Center for Mineral Metabolism and Clinical Research, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Mingjun
authors.initials: M
authors.lastname: Shi
authors.affiliation: Charles and Jane Pak Center for Mineral Metabolism and Clinical Research, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Nancy
authors.initials: N
authors.lastname: Gillings
authors.affiliation: Charles and Jane Pak Center for Mineral Metabolism and Clinical Research, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Brianna
authors.initials: B
authors.lastname: Flores
authors.affiliation: Department of Radiology, University of Texas Southwestern Medical Center, Dallas, Texas, USA; Advanced Imaging Research Center, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Masaya
authors.initials: M
authors.lastname: Takahashi
authors.affiliation: Charles and Jane Pak Center for Mineral Metabolism and Clinical Research, University of Texas Southwestern Medical Center, Dallas, Texas, USA; Center for Molecular Medicine, Jichi Medical University, Tochigi, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Kuro-O
authors.affiliation: Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA; Charles and Jane Pak Center for Mineral Metabolism and Clinical Research, University of Texas Southwestern Medical Center, Dallas, Texas, USA; Department of Physiology, University of Texas Southwestern Medical Center, Dallas, Texas, USA. Electronic address: orson.moe@utsoutwestern.edu.
authors.forename: Orson W
authors.initials: OW
authors.lastname: Moe
mesh_terms: D058186:Acute Kidney Injury / Q000097:blood / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism; D000818:Animals; D001691:Biological Therapy / Q000379:methods; D009202:Cardiomyopathies / Q000188:drug therapy* / Q000209:etiology; D004195:Disease Models, Animal; D018450:Disease Progression; D004353:Drug Evaluation, Preclinical; D005260:Female; D005355:Fibrosis; D005966:Glucuronidase / Q000008:administration & dosage / Q000378:metabolism* / Q000627:therapeutic use*; D006801:Humans; D007274:Injections, Intraperitoneal; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D000090265:Klotho Proteins; D008297:Male; D051379:Mice; D009206:Myocardium / Q000473:pathology; D011994:Recombinant Proteins / Q000627:therapeutic use; D051436:Renal Insufficiency, Chronic / Q000097:blood / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism; D014511:Uremia / Q000150:complications
chemical_list: D011994:Recombinant Proteins; D005966:Glucuronidase; D000090265:Klotho Proteins
keywords: acute kidney injury; cardiovascular disease; chronic kidney disease; ischemia reperfusion; phosphate