EXPERIMENTAL AND MOLECULAR PATHOLOGY 4, 21-28 (1986) Renal Histamine increases in the Streptozotocin-Diabetic Rat’ RONALD A. MARKLE,~ THEODORE M. HOLLIS,~ AND ANDREW J. COSGAREA~ ‘Department of Biological Sciences, Northern Arizona University, Flagstaff, Arizona 86011, and ‘Department of Biology, The Pennsylvania State University, 208 Mueller Laboratory, University Park, Pennsylvania 16802 Received July 25, 1985, and in revised form September 30, 1985 Renal histamine concentration, total histamine and protein contents were measured in rats made diabetic via iv streptozotocin injection and held for 13 weeks following diagnosis of diabetes. Insulin (7 U/day) or cx-hydrazinohistidine (a-HH, 25 mgikglday) or both drugs were administered to diabetic subgroups the last 2 weeks of the holding period. Untreated diabetics developed significant increases of renal histamine concentration and total hista- mine content, up 45 and 46%, respectively. Drug interventions reduced the diabetic in- creases of histamine concentration and content (in order) as follows: diabetic-insulin, down 7 and 8%; diabetic-u-HH down 25 and 26%; diabetic-insulin + a-HH, down 35 and 36%. Renal tissue protein content was unchanged and qualitative proteinuria was present in all diabetic subgroups. The data indicate that in experimental diabetes there is an increase of the renal inducible histamine pool which is partially reduced by insulin and/or a-HH treat- ments. In view of the long-recognized actions of histamine upon microvascular permeability, elevated renal histamine may be one pathophysiological mediator of the diabetic functional renal microangiopathy manifest as proteinuria. 6 1986 Academic PKSS, Inc. INTRODUCTION Vascular lesions of both large muscular arteries and capillaries represent major clinical complications of the chronic diabetic state (see Stout, 1979 for summary). The macroangiopathy is manifest as accelerated atherosclerosis; the microangiop- athy is most prevalent in retinal and renal tissues (Brownlee and Cahill, 1979). In addition to the long-recognized morphological alterations in the diabetic kidney (Kimmelstiel and Wilson, 1936) a functional microangiopathy, manifest as pro- teinuria, has been described in human studies of short-term juvenile diabetics (Parving et al., 1976) and so-called adult prediabetics (Keen and Chlouverkis, 1964), and these preceding studies postulate that an increased porosity of the microvasculature may be responsible for the proteinuria. However, a triggering mechanism for such enhanced permeability is not defined. In recent years, Hollis and co-workers have reported alterations of aortic wall histamine metabolism and macromolecular permeability in the streptozotocin di- abetic rat. Two principal findings have been consistent increases of (1) histamine content and (2) de ltovo histamine synthesis observed in isolated aortic endothe- lium and smooth muscle cells (Orlidge and Hollis, 1982; Hollis et al., 1983) or aortic intima-media (Carroll and Hollis, 1985; Hollis and Strickberger, 1985). In untreated diabetic rats, enhanced aortic permeability to fluorescein-labeled al- bumin correlated with aortic histamine content (Hollis et al., 1983; Carroll and Hollis, 1985), and this enhanced permeability was ameliorated by administration * Supported by University Organized Research of Northern Arizona University (R.A.M.), and NIH Grant HL 20460 and the Coronary Heart Disease Research Project, a Program of the American Health Assistance Foundation (T.M.H.). 0014-4800/86 $3.00 Copyright 0 1986 by Academic Press, Inc. All rights of reproduction in any form reserved.