Cisplatin nephrotoxicity as a model of chronic kidney disease

Mingjun Shi, Kathryn L. McMillan, Junxia Wu, Nancy Gillings, Brianna Flores, Orson W Moe, Ming C Hu

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Cisplatin (CP)-induced nephrotoxicity is widely accepted as a model for acute kidney injury (AKI). Although cisplatin-induced chronic kidney disease (CKD) in rodent has been reported, the role of phosphate in the cisplatin-induced CKD progression is not described. In this study, we gave a single peritoneal injection of CP followed by high (2%) phosphate diet for 20 weeks. High dose CP (20 mg/Kg) led to high mortality; whereas a lower dose (10 mg/Kg) resulted in a full spectrum of AKI with tubular necrosis, azotemia, and 0% mortality 7 days after CP injection. After consuming a high phosphate diet, mice developed CKD characterized by low creatinine clearance, interstitial fibrosis, hyperphosphatemia, high plasma PTH and FGF23, low plasma 1,25(OH)2 Vitamin D3 and αKlotho, and classic uremic cardiovasculopathy. The CP model was robust in demonstrating the effect of aging, sexual dimorphism, and dietary phosphate on AKI and also AKI-to-CKD progression. Finally, we used the CP-high phosphate model to examine previously validated methods of genetically manipulated high αKlotho and therapy using exogenous soluble αKlotho protein supplementation. In this CP CKD model, αKlotho mitigated CKD progression, improved mineral homeostasis, and ameliorated cardiovascular disease. Taken together, CP and high phosphate nephrotoxicity is a reproducible and technically very simple model for the study of AKI, AKI-to-CKD progression, extrarenal complications of CKD, and for evaluation of therapeutic efficacy.

Original languageEnglish (US)
Pages (from-to)1-17
Number of pages17
JournalLaboratory Investigation
DOIs
StateAccepted/In press - Jun 1 2018

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Chronic Renal Insufficiency
Cisplatin
Acute Kidney Injury
Phosphates
Disease Progression
Diet
Hyperphosphatemia
Azotemia
Injections
Mortality
Cholecalciferol
Sex Characteristics
Minerals
Rodentia
Creatinine
Homeostasis
Fibrosis
Necrosis
Cardiovascular Diseases
Therapeutics

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Molecular Biology
  • Cell Biology

Cite this

Cisplatin nephrotoxicity as a model of chronic kidney disease. / Shi, Mingjun; McMillan, Kathryn L.; Wu, Junxia; Gillings, Nancy; Flores, Brianna; Moe, Orson W; Hu, Ming C.

In: Laboratory Investigation, 01.06.2018, p. 1-17.

Research output: Contribution to journalArticle

Shi, Mingjun ; McMillan, Kathryn L. ; Wu, Junxia ; Gillings, Nancy ; Flores, Brianna ; Moe, Orson W ; Hu, Ming C. / Cisplatin nephrotoxicity as a model of chronic kidney disease. In: Laboratory Investigation. 2018 ; pp. 1-17.
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