Mediators and mechanisms of radiation nephropathy

Normal tissue radiation injury occurs after sufficient irradiation, thus li miting the curative potential of x-ray therapy. In the kidney, radiation in jury results in fibrosis and, ultimately, renal failure. The mediators of f ibrosis in radiation nephropathy have received scant attention. Therefore, we evaluated the sequential presence of alpha smooth muscle actin (alpha sm a), fibrin, collagen, and TGF beta(1) in a porcine model of radiation nephr opathy using 9.8 Gy single-dose local kidney irradiation. During the 24-wee k study, there was progressive and significant collagen accumulation in glo meruli and in interstitium. In glomeruli, this was associated with signific ant mesangial alpha sma expression by 2 weeks after irradiation, a further rise at 4 weeks, and then a gradual fall to baseline. Glomerular fibrin dep osition was significant by 4 weeks after irradiation, and remained elevated thereafter. There was little or no glomerular TGF beta(1) expression at an y time point. Tubular fibrin deposition was significant at 4 weeks after ir radiation but declined thereafter. There was little or no tubulo-interstiti al alpha sma expression at any time after irradiation. At 6 weeks after irr adiation, there was a significant peak of tubular epithelial TGF beta(1) ex pression that declined thereafter. The early glomerular injury is evident a s mesangial asma expression but is not proceeded by TGF beta(1) expression. There is sustained glomerular fibrin deposition with deposition of fibrin in tubular lumens, suggesting that tubular fibrin derives and flows out fro m injured glomerular tufts. We conclude that i) alpha 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 ) TGF beta(1) is not an early event in radiation nephropathy, and not appar ent in glomeruli in this model, but may correlate with later tubulo-interst itial fibrosis. Thus, the mediators of scarring in this model differ accord ing to time after injury and also according to the affected tissue compartm ent.