Bone Marrow–Derived Myofibroblasts Contribute to the Renal... : Journal of the American Society of Nephrology (original) (raw)

Pathophysiology of Renal Disease and Progression

Bone Marrow–Derived Myofibroblasts Contribute to the Renal Interstitial Myofibroblast Population and Produce Procollagen I after Ischemia/Reperfusion in Rats

Broekema, Martine*; Harmsen, Martin C.*; van Luyn, Marja J.A.*; Koerts, Jasper A.*; Petersen, Arjen H.*; van Kooten, Theo G.†; van Goor, Harry‡; Navis, Gerjan§; Popa, Eliane R.*

*Department of Pathology & Laboratory Medicine, Medical Biology Section, and Departments of †Biomedical Engineering, ‡Pathology, and §Nephrology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands

Address correspondence to: Martine Broekema, University Medical Center Groningen, University of Groningen, Department of Pathology & Laboratory Medicine, Medical Biology Section, Hanzeplein 1, Room Z 2.09, 9713 GZ Groningen, The Netherlands. Phone: +31-50-3632417; Fax: +31-50-3619911; E-mail: [email protected]

Accepted October 11, 2006

Received July 15, 2005

Abstract

Bone marrow–derived cells (BMDC) have been proposed to exert beneficial effects after renal ischemia/reperfusion injury (IRI) by engraftment in the tubular epithelium. However, BMDC can give rise to myofibroblasts and may contribute to fibrosis. BMDC contribution to the renal interstitial myofibroblast population in relation to fibrotic changes after IRI in rats was investigated. A model of unilateral renal IRI (45 min of ischemia) was used in F344 rats that were reconstituted with R26-human placental alkaline phosphatase transgenic BM to quantify BMDC contribution to the renal interstitial myofibroblast population over time. After IRI, transient increases in collagen III transcription and interstitial protein deposition were observed, peaking on days 7 and 28, respectively. Interstitial infiltrates of BMDC and myofibroblasts reached a maximum on day 7 and gradually decreased afterward. Over time, an average of 32% of all interstitial α-smooth muscle actin–positive myofibroblasts coexpressed R26-human placental alkaline phosphatase and, therefore, were derived from the BM. BMD myofibroblasts produced procollagen I protein and therefore were functional. The postischemic kidney environment was profibrotic, as demonstrated by increased transcription of TGF-β and decreased transcription of bone morphogenic protein-7. TGF-β protein was present predominantly in interstitial myofibroblasts but not in BMD myofibroblasts. In conclusion, functional BMD myofibroblasts infiltrate in the postischemic renal interstitium and are involved in extracellular matrix production.