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Original Article

Mediators and Mechanisms of Radiation Nephropathy

Eric P. Cohen^*,1, Stephen A. Bonsib, Elizabeth Whitehouse, John W. Hopewell and Mike E. C. Robbins^,

^* Medical College of Wisconsin, Froedtert Memorial Lutheran Hospital, Milwaukee, WI 53226;
University of Iowa, Iowa City, Iowa 52242; and
University of Oxford, Oxford, England, OX1 2JD

Normal tissue radiation injury occurs after sufficient irradiation, thus limiting the curative potential of x-ray therapy. In the kidney, radiation injury results in fibrosis and, ultimately, renal failure. The mediators of fibrosis in radiation nephropathy have received scant attention. Therefore, we evaluated the sequential presence of alpha smooth muscle actin (sma), fibrin, collagen, and TGFß₁ in a porcine model of radiation nephropathy using 9.8 Gy single-dose local kidney irradiation. During the 24-week study, there was progressive and significant collagen accumulation in glomeruli and in interstitium. In glomeruli, this was associated with significant mesangial sma expression by 2 weeks after irradiation, a further rise at 4 weeks, and then a gradual fall to baseline. Glomerular fibrin deposition was significant by 4 weeks after irradiation, and remained elevated thereafter. There was little or no glomerular TGFß₁ expression at any time point. Tubular fibrin deposition was significant at 4 weeks after irradiation but declined thereafter. There was little or no tubulo-interstitial sma expression at any time after irradiation. At 6 weeks after irradiation, there was a significant peak of tubular epithelial TGFß₁ expression that declined thereafter. The early glomerular injury is evident as mesangial sma expression but is not proceeded by TGFß₁ expression. There is sustained glomerular fibrin deposition with deposition of fibrin in tubular lumens, suggesting that tubular fibrin derives and flows out from injured glomerular tufts. We conclude that i) sma expression is an early marker of glomerular radiation injury, presaging scarring; ii) fibrin deposition is involved in glomerular and tubular radiation injury; and iii) TGFß₁ is not an early event in radiation nephropathy, and not apparent in glomeruli in this model, but may correlate with later tubulo-interstitial fibrosis. Thus, the mediators of scarring in this model differ according to time after injury and also according to the affected tissue compartment.

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