Recombinant α-Klotho may be prophylactic and therapeutic for acute to chronic kidney disease progression and uremic cardiomyopathy

Ming C Hu, Mingjun Shi, Nancy Gillings, Brianna Flores, Masaya Takahashi, Makoto Kuro-o, Orson W Moe

Research output: Contribution to journalArticle

55 Citations (Scopus)

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.

Original languageEnglish (US)
JournalKidney International
DOIs
StateAccepted/In press - Jul 11 2016

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Cardiomyopathies
Chronic Renal Insufficiency
Disease Progression
Acute Kidney Injury
Kidney
Therapeutics
Clinical Protocols
Reperfusion Injury
Preexisting Condition Coverage
Wounds and Injuries
Cardiovascular System
Nephrectomy
Recombinant Proteins
Fibrosis
Cardiovascular Diseases
Phosphates
Diet

Keywords

  • Acute kidney injury
  • Cardiovascular disease
  • Chronic kidney disease
  • Ischemia reperfusion
  • Phosphate

ASJC Scopus subject areas

  • Medicine(all)
  • Nephrology

Cite this

Recombinant α-Klotho may be prophylactic and therapeutic for acute to chronic kidney disease progression and uremic cardiomyopathy. / Hu, Ming C; Shi, Mingjun; Gillings, Nancy; Flores, Brianna; Takahashi, Masaya; Kuro-o, Makoto; Moe, Orson W.

In: Kidney International, 11.07.2016.

Research output: Contribution to journalArticle

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