CHRONIC OBSTRUCTIVE UROPATHY IN SEVERE COMBINED IMMUNODEFICIENT (SCID) MICE - LYMPHOCYTE INFILTRATION IS NOT REQUIRED FOR PROGRESSIVE TUBULOINTERSTITIAL INJURY

Progressive renal injury in humans and experimental animal models is c haracterized by tubular atrophy, infiltration of mononuclear inflammat ory cells, and interstitial fibrosis. Permanent unilateral ureter liga tion represents a reproducible model for investigating mechanisms of p rogressive kidney injury, and in the rat is characterized by tubular e pithelial cell proliferation followed by apoptosis and progressive inf iltration of monocytes and lymphocytes. Nevertheless, whether monocyte s or lymphocytes play a dominant role in causing tubulointerstitial da mage remains to be elucidated. In the current study, a model of chroni c obstructive uropathy in the mouse is established and the role of lym phocyte infiltration in the evolution of the tubule and interstitial a lterations is investigated. Permanent ligation of the left ureter in w ild-type (C3H/HeJ) mice resulted in progressive atrophy of tubules and interstitial fibrosis compared with the contralateral kidney over a 3 0-d period. Immunoperoxidase studies on frozen sections taken from kid neys at 0, 3, 10, 20, and 30 d after ureter ligation showed that the t ubulointerstitial injury was accompanied by a marked and progressive i ncrease in interstitial macrophages and T lymphocytes, with no appreci able increase in B lymphocytes. No increase in inflammatory cells was detected in contralateral kidneys over the same lime frame. The signif icance of T lymphocyte infiltration was examined by comparing the degr ee of tubular atrophy and interstitial fibrosis and the nature and qua ntity of the inflammatory infiltrate in wild-type mice and C3HSMn.C-Sc id/J (SCID) mice subjected to permanent left ureter ligation. SCID mic e have genetic defects in immunoglobulin and T cell receptor gene rear rangements and are devoid of circulating mature B and T lymphocytes. W ild-type and SCID mice developed tubular atrophy and interstitial volu me expansion in the ligated kidney to the same degree and at the same rate. SCID mice developed a prominent and marked monocyte/macrophage i nfiltrate in the ligated kidney, which was essentially equal to that i n wild-type mice. In contrast, consistent with the known absence of ma ture lymphocytes in SCID mice, there was essentially no T lymphocyte i nfiltration into the ligated kidney of SCID mice. These results demons trate the effective establishment of the model of maintained unilatera l ureter ligation in mice, which is readily applicable to genetic muta nt strains thus allowing for specific investigation of the role of ind ividual components of the inflammatory response in progressive tubuloi nterstitial injury. These studies further demonstrate that lymphocyte infiltration is not required for progressive tubular atrophy and incre ased Interstitial fibrosis after maintained unilateral ureter ligation .