Vasopressin contributes to hyperfiltration, albuminuria, and renal hypertrophy in diabetes mellitus: Study in vasopressin-deficient Brattleboro rats

Abstract

Diabetic nephropathy represents a major complication of diabetes mellitus (DM), and the origin of this complication is poorly understood. Vasopressin (VP), which is elevated in type I and type II DM, has been shown to increase glomerular filtration rate in normal rats and to contribute to progression of chronic renal failure in 5͞6 nephrectomized rats. The present study was thus designed to evaluate whether VP contributes to the renal disorders of DM. Renal function was compared in Brattleboro rats with diabetes insipidus (DI) lacking VP and in normal Long-Evans (LE) rats, with or without streptozotocin-induced DM. Blood and urine were collected after 2 and 4 weeks of DM, and creatinine clearance, urinary glucose and albumin excretion, and kidney weight were measured. Plasma glucose increased 3-fold in DM rats of both strains, but glucose excretion was Ϸ40% lower in DI-DM than in LE-DM, suggesting less intense metabolic disorders. Creatinine clearance increased significantly in LE-DM (P < 0.01) but failed to increase in DI-DM. Urinary albumin excretion more than doubled in LE-DM but rose by only 34% in DI-DM rats (P < 0.05). Kidney hypertrophy was also less intense in DI-DM than in LE-DM (P < 0.001). These results suggest that VP plays a critical role in diabetic hyperfiltration and albuminuria induced by DM. This hormone thus seems to be an additional risk factor for diabetic nephropathy and, thus, a potential target for prevention and͞or therapeutic intervention.One of the major complications of diabetes mellitus (DM) is a progressive nephropathy that develops in about one-third of patients within 10-20 years after the onset of the disease and leads in most cases to end stage renal failure (1). This represents a major problem of public health because a large fraction of dialysis requirements is attributable to DM nephropathy. Although a number of studies have already been devoted to this problem, the factors contributing to diabetic nephropathy are not yet fully identified.A characteristic feature observed in diabetic patients is an elevation of plasma vasopressin (VP), well documented in both type I and type II DM (2-5). This elevation also occurs in animal models of DM, whether experimental or genetically determined (6, 7). Several studies have investigated the possible factors responsible for this increase in VP secretion (3,6,8,9). But they did not succeed in identifying the responsible stimulus for this increase. They revealed a resetting of the osmostat in diabetics but concluded that hyperglycemia was not responsible for this resetting because increasing plasma glucose and osmolality by intravenous infusion of hypertonic dextrose produced no increase in plasma vasopressin in diabetics or in healthy controls (8).Little attention has been given to the possible functional consequences of the rise in plasma VP. To our knowledge, the possible contribution of VP to the renal complications of DM has never been investigated in spite of several previous findings suggesting that this hormone represents a ...

Aquaporin-2 and urea transporter-A1 are up-regulated in rats with Type I diabetes mellitus

“…This increase occurs in a situation characterised by an enhanced vasopressin secretion [1±3] and an increased need for water conservation. Actually, as already mentioned [9,10], the diabetic kidney achieves a considerable success in concentrating a large amount of glucose in the urine. This is evidenced by the 4.4-fold higher solute-free water reabsorption occurring in diabetic rats compared with control rats, even though urine flow rate is increased and urine osmolality decreased.…”

“…Recent studies have revealed that the diabetic kidney displays an increased (not a decreased) urinary concentrating activity. Although urine flow rate is much increased and urine osmolality modestly decreased, the amount of free water that the kidney reabsorbs in order to excrete the actual load of solutes, the solute-free water reabsorption, is largely enhanced in diabetes mellitus [9,10].…”

Mild dehydration, vasopressin and the kidney: animal and human studies

“…At 4 weeks after inducing of diabetes, the glomerular filtration rate rose significantly in the Long-Evans rats but not in the Brattleboro rats, even though they had similar blood glucose values. Urine albumin excretion, which reflects the degree of glomerular damage and renal mass, increased much less in rats without vasopressin than those with endogenous vasopressin (Bardoux et al, 1999) (Figure 7). In another experiment, we showed that albuminuria was prevented during experimental diabetes in Wistar rats when a V2 receptor antagonist was administered for several weeks (Bardoux et al, 2003).…”

“…In some studies, vasopressin has been reported to have a natriuretic effect, but this was observed only when intense Creatinine clearance and urinary albumin excretion in control (cont) and diabetic (DM) rats with (Long-Evans) or without (Brattleboro) endogenous vasopressin, 4 weeks after induction of diabetes. Mean7SEM, n¼7-8 per group, **Po0.01, ***Po0.001, adapted from Bardoux et al (1999). diuresis was interrupted by the systemic infusion of vasopressin, resulting in a volume expansion (Walter et al, 1996).…”

Histopathological Study of Kidney Abnormalities in an Experimental SIADH Rat Model and Its Application to the Evaluation of the Pharmacologic Profile of VP-343, a Selective Vasopressin V2 Receptor Antagonist.

“…6,7) Vasopressin antagonists were reported to affect the levels of triglyceride, systolic blood pressure, serum creatinine, and the histopathologic index of glomerular sclerosis in progressive glomerulosclerosis in spontaneously hypercholesteromic rats. 8,9) Therefore vasopressin antagonists could be expected to exhibit a therapeutic effect on the kidney in SIADH rats.…”