Impaired response to angiotensin II in Type 1 (insulin-dependent) diabetes mellitus. Role of prostaglandins and sodium-lithium countertransport activity

Abstract

The pathogenesis of diabetic nephropathy remains elusive. A role for renal prostaglandins in antagonizing the hormonal effects of renin-angiotensin II has been postulated as a putative factor leading to hyperfiltration in patients with Type 1 (insulin-dependent) diabetes mellitus. Our aim was to elucidate the effects of angiotensin II on kidney haemodynamics and on blood pressure in eight normal subjects, in nine normotensive, in nine hypertensive with normal sodium-lithium countertransport activity in erythrocytes, in seven hypertensive without and in eight hypertensive Type 1 diabetic patients with microalbuminuria and with high sodium-lithium countertransport activity in erythrocytes. Angiotensin II infusion (4 ng.kg-1.min-1 for 60 min) decreased the glomerular filtration rate to a greater extent in normal subjects (-20%), than in normotensive patients (-5% p less than 0.01), in hypertensive patients with normal sodium-lithium countertransport activity in erythrocytes (-8% p less than 0.01) in hypertensive patients with high sodium-lithium countertransport (-6% p less than 0.01) and in hypertensive microalbuminuric patients (-5% p less than 0.01) with Type 1 diabetes. The urinary excretion rate of vasodilatory prostaglandins was two-three fold higher in all patients than in normal subjects. Acute indomethacin treatment restored a normal response to angiotensin II infusion in normotensive patients, but did not change the renal haemodynamic response in normal subjects. With regard to hypertensive patients with and without microalbuminuria indomethacin treatment restored a normal response to angiotensin II in some but not all patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Reduced Renal Microvascular Reactivity to Angiotensin II in Diabetic Rats

“…Our observations made 7-10 days after induction of diabetes agree with the conclusion of Sarubbi and colleagues (31) that a substantial decline in renal reactivity occurs between 5 and 14 days of streptozotocin-induced diabetes. A diminished renal arteriolar response to Ang I1 also corroborates other studies of human (15) and experimental diabetes (29,37); like these results from hydronephrotic kidneys (Fig. l) First, a reduced glomerular receptor density (2,38), if also applicable to the microvessels, would lead to a reduced arteriolar constrictor response.…”

“…The numerous mechanisms that may account for the low resistance of renal microvessels in diabetes include alterations in the renin-angiotensin system (1, 3 , 19). Evidence that human (15) and experimental (29,31) diabetic subjects exhibit an impaired renal vascular response to angiotensin I1 (Ang 11) led to speculation that a diminished constrictor response could contribute to the loss of blood flow control (18,20,27,40). Overproduction of vasodilator prostaglandins in diabetic kidneys (13,14,26,32) suggested that prostaglandins might also play a role in the hyperfiltration via direct arteriolar dilation and/or attenuation of vascular responsiveness to Ang 11.…”

In Vivo Fluorescence Microscopy of Microcirculation in the Renal Cortex of Mice

“…The renal synthesis of prostaglandins is frequently increased in subjects with short-term insulin-dependent diabetes mellitus (IDDM) (9, 43) making them less susceptible to infusions of vasoconstrictor agents (8).…”

Peripheral macro‐and microcirculation in short‐term insulin‐dependent diabetes mellitus: the role of prostaglandins in early haemodynamic changes

“…The changes in baseline CBV after ASA, however, should be interpreted with caution, due to the small sample sizes and wide variation in data. In short-term diabetes, renal hyperperfusion and hyperfiltration are partly due to elevated prostacyclin production [13,34,35]. We demonstrated previously that inhibition of prostaglandin synthesis reduces hyperfiltration [36].…”