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Published on: September 1, 2016
Osteogenic Protein-1: gene expression and treatment in rat remnant kidney model
Philip H Dube1, Maria M Almanzar, Kendall S Frazier
1Department of Nephrology, Miami Children's Hospital, Miami, Florida, USA.
Abstract:
Osteogenic Protein-1 (OP-1) is a bone morphogen involved in tissue repair and development. We have shown that OP-1 is downregulated during acute ischemic renal injury. Here we report the use of the rat remnant kidney model (RRKM) to evaluate changes in kidney OP-1 expression during chronic injury, and determine if treatment with recombinant human OP-I (rhOP-1) aids in recovery from injury. Sprague-Dawley rats were subjected to kidney decapsulation (Cx) or 5/6 nephrectomy (Nx). Serum for BUN and creatinine and tissue for histology and mRNA analysis were collected at: 2, 10. and 12-14 wks post Nx. We show kidney OP-1 mRNA levels were downregulated at 2 and 12-14 wks post Nx. To determine the effect of rhOP-1 in the RRKM, rhOP-1 (0.25, 2.5 or 25 microg/kg) or vehicle (V) was injected in a second set of rats, 2 weeks after 2/3 left Nx for a total of six doses. Nx rats treated with rhOP-1 showed significantly increased tubular regeneration (increased mitotic figures, polyoid infolding, and tubular epithelialhyperplasia) in a dose dependent manner without changes in glomerular or tubular damage. rhOP-1 stimulates tubular epithelial cell regeneration,early in the repair process in a chronic renal failure model, before significant fibrosis is established.
Insights
Osteogenic Protein-1 (OP-1) is downregulated in chronic kidney injury. Recombinant human OP-1 (rhOP-1) treatment promoted tubular regeneration in a rat model, suggesting a therapeutic potential for kidney repair.
Area of Science:
- Nephrology
- Regenerative Medicine
- Molecular Biology
Background:
- Osteogenic Protein-1 (OP-1) is a bone morphogen crucial for tissue repair and development.
- OP-1 expression is reduced during acute ischemic renal injury.
- The rat remnant kidney model (RRKM) is used to study chronic kidney injury.
Purpose of the Study:
- To investigate changes in kidney OP-1 expression during chronic injury using the RRKM.
- To evaluate the efficacy of recombinant human OP-1 (rhOP-1) in promoting recovery from chronic kidney injury.
Main Methods:
- Sprague-Dawley rats underwent 5/6 nephrectomy (Nx) to induce chronic kidney injury.
- Kidney tissue and serum were collected at various time points for mRNA analysis and biochemical assays (BUN, creatinine).
- rhOP-1 or vehicle was administered to Nx rats to assess its therapeutic effect on tubular regeneration.
Main Results:
- Kidney OP-1 mRNA levels were significantly downregulated at 2 and 12-14 weeks post-Nx.
- rhOP-1 treatment dose-dependently increased tubular regeneration, evidenced by increased mitotic figures and tubular epithelial hyperplasia.
- No significant changes in glomerular or tubular damage were observed with rhOP-1 treatment.
Conclusions:
- OP-1 is downregulated in a chronic renal failure model.
- rhOP-1 stimulates tubular epithelial cell regeneration early in the repair process of chronic kidney injury.
- rhOP-1 shows potential as a therapeutic agent for promoting kidney repair before significant fibrosis develops.
