Fetal partial urethral obstruction causes renal fibrosis and is associatedwith proteolytic imbalance

Purpose: We determine whether fetal bladder outlet obstruction induces rena l fibrosis, and is associated with an alteration in the regulation of conne ctive tissue degradation and the presence of fibrogenic interstitial cells. Materials and Methods: Partial bladder outlet obstruction was surgically in duced in 33 fetal sheep at 95 days of gestation. These animals and 24 norma l age matched controls were sacrificed at 109, 116 and 135 (term) days of g estation, and the kidneys were rapidly retrieved, drained and weighed. Repr esentative whole kidney samples were snap frozen for assessment of deoxyrib onucleic acid, protein and collagen content. Morphometric analysis and ct-s mooth muscle actin immunohistochemistry were performed on histological spec imens from formalin fixed kidneys. Tissue extract from fresh kidney specime ns were analyzed for metalloproteinase and tissue inhibitor of metalloprote inase activity. Urine samples obtained at the time of sacrifice were analyz ed for electrolyte, creatinine and N-acetyl glucosaminidase excretion. Results: All obstructed kidneys were hydronephrotic and larger than age mat ched controls. Obstructed kidneys at term showed interstitial fibrosis, as measured by increased extracellular matrix volume fraction (45% in male obs tructed kidneys versus 2.5% in normal male kidneys, p = 0.0004), increased total collagen content (120 mg./kidney in male obstructed versus 20 mg. in normal male animals, p = 0.016) and collagen/deoxyribonucleic acid content per kidney (2.78 versus 0.53 mg./mg., p = 0.016). Metalloproteinase-l activ ity was significantly lower in obstructed kidneys (210 versus 380 U./mg. pr otein in normal kidneys). Tissue inhibitor of metalloproteinase activity wa s undetectable in both groups. The presence of an increased population of m yofibroblasts often associated with fibrotic processes was seen by ct-smoot h muscle actin staining which was localized to interstitial cells throughou t the cortex in obstructed kidneys. Conclusions: Fetal partial bladder outlet obstruction induces renal interst itial fibrosis as early as 2 weeks after obstruction. A possible mechanism for this process is a shift in proteolytic activity to reduce matrix degrad ation in obstructed kidneys. These changes might be mediated by the increas ed number of fibrogenic interstitial cells. The observations suggest severa l potential approaches to developing an understanding of congenital obstruc tive uropathy.