Nonanticoagulant Protective Effect of Heparin in Chronic Aminonucleoside Nephrosis

Abstract

Aminonucleoside nephrosis progresses over an 18-week period to focal and segmental glomerulosclerosis (FSGS). Whole heparin has been shown to blunt the extent of renal injury in another model of FSGS, renal ablation; however, the precise mechanism of protection has remained uncertain. Since heparin has a variety of physiologie actions unrelated to anticoagulation, we administered three different heparin compounds, each with a distinct profile of biological properties, to groups of rats given a single intravenous dose of puromycin aminonucleoside (PA). In the absence of a prolongation of the activated partial thromboplastin time (aPTT), both whole heparin (WH) and a 7,000- to 11,000-dalton-molecular-weight nonanticoagulant heparin (NAH) ameliorated the functional and histologic abnormalities of chronic aminonucleoside nephrosis as evidenced by significant reductions in 24-hour urine protein excretion while preserving the glomerular filtration rate and blunting the rise in serum creatinine as compared to untreated PA control animals at the conclusion of the study. In addition, the NAH and WH groups exhibited significantly fewer glomeruli with either segmental mesangial proliferative areas or glomerulosclerosis/hyalinosis lesions 18 weeks after PA administration. A fragment of heparin (HF) was ineffective. We conclude that heparin may exert its beneficial effect in chronic aminonucleoside nephrosis through a biologic action, other than anticoagulation, perhaps by inhibition of mesangial cell proliferation.

Mechanisms underlying transition from acute glomerular injury to late glomerular sclerosis in a rat model of nephrotic syndrome.

“…This model also differs from that produced by adriamycin, which induces nephrotic syndrome but not severe renal insufficiency (35,36), and from other experimental glomerulonephritides (13,14), which feature renal insufficiency but not nephrotic syndrome. Interestingly, this model also differs from that which occurs using the same PA dosing regimen in Sprague-Dawley rats (1)(2)(3)(4), in that the Munich-Wistar rats exhibit markedly more severe renal insufficiency, morphologic injury, and nephrotic syndrome than do the apparently less susceptible Sprague-Dawley rats. Although initial (phase I) and recurrent (phase III) proteinuria and glomerular sclerosis are of comparable magnitude in the two strains, the SpragueDawley rat develops sclerosis much earlier, but with negligible tubulointerstitial abnormalities, suggesting differences in both susceptibility to, and sequellae after, acute injury between the two strains.…”

“…Although more extreme, this hemodynamic pattern of decreased SNGFR, SNFF, and Kf is similar to that reported in nonnephrotic rats administered lower doses of PA (1 1, 12). 2 The role of reduced serum albumin and plasma oncotic pressure was further addressed in studies of four nephrotic rats which received normal plasma, rather than nephrotic plasma, to replace surgical losses during the experiment. In these rats, values for serum protein concentration were raised toward (5.0±0.3 g/dl) although not to normal levels.…”

Heparin Prevents Intracellular Hyaluronan Synthesis and Autophagy Responses in Hyperglycemic Dividing Mesangial Cells and Activates Synthesis of an Extensive Extracellular Monocyte-adhesive Hyaluronan Matrix after Completing Cell Division

“…Heparin treatment suppressed the formation of hypercellular mesangial nodules in the focal mesangio-proliferative disease induced by injecting Habu snake venom into rats (13). It also reduces the mesangial hypercellularity that develops in chronic aminonucleoside nephrosis (14), but it does not affect endocapillary proliferation in the progressive Masugi nephritis model (18). Particularly pertinent to this study, heparin has been shown to prevent albuminuria and mesangial expansion in diabetic rats (11,12) and to suppress mesangial cell proliferation and matrix expansion in experimental mesangio-proliferative glomerulonephritis (19).…”

“…It is synthesized as a proteoglycan (serglycin) that is found in mast cells. Heparin has been shown to inhibit mesangial cell growth in both experimental renal disease models (11)(12)(13)(14)(15) and in cell culture (16,17). Heparin treatment suppressed the formation of hypercellular mesangial nodules in the focal mesangio-proliferative disease induced by injecting Habu snake venom into rats (13).…”

A Pathologist's Odyssey

“…Furthermore, the chronic phase of our glomerular nephritis model referred to above (28), in which there is mesangial cell proliferation, was prevented by administration of a nonanticoagulant, antiproliferative heparin derivative, as well as by whole heparin (42), and proteinuria was markedly diminished.…”