Angiotensin II and eicosanoids in the control of glomerular size in the rat and human

Abstract

We examined the possibility that glomerular prostaglandin E2 (PGE2) regulates the action of angiotensin II (ANG II) on mesangial contraction and filtration surface area. Using isolated rat glomeruli we indirectly assessed mesangial contraction and filtration surface area through measurements of glomerular planar surface area (GPSA) by image-analysis microscopy. ANG II reduced GPSA by approximately 20% in human and rat glomeruli, with threshold concentrations of 1 X 10(-13) M and maximum effect at 5 X 10(-11) M ANG II. Inhibition of glomerular PG synthesis with indomethacin or meclofenamate potentiated the threshold response of ANG II to reduce GPSA. Arachidonic acid (5 micrograms/ml) blunted both the threshold and the maximum responses of GPSA to ANG II. PGE2, 10(-8) and 10(-9) M, also decreased glomerular contraction to ANG II. Endoperoxide (EP) analogues decreased GPSA and EP 045, a thromboxane A2 (TXA2) receptor blocker, eliminated the contractile responses of glomeruli to the EP analogues. Authentic TXA2, synthesized from sheep platelet microsomes, also reduced GPSA. We conclude that glomerular products of arachidonate cyclooxygenation may either relax or contract the mesangium, thereby preserving or reducing filtration surface area. PGE2 exerts protective actions to reduce the mesangial contraction of ANG II, primarily through postreceptor effects. TXA2 may decrease glomerular filtration rate in certain diseases through direct actions on the mesangium.

Eicosanoids, Mesangial Contraction, and Intracellular Signal Transduction.

“…Although there is no direct proof of such hemodynamic function of mesangial cells, various observations are consistent with this model, including measurements of selective changes of K f upon infusion of vasoactive agents (Blantz et al 1976 ; Ichikawa and Brenner 1979 ;Schor et a1.1981) or in glomerulonephritis (Maddox et al 1975). Moreover, studies in freshly isolated rat and human gomeruli indicate the presence of a contractile apparatus mediating rapid dimensional changes of the tuft upon exposure to vasoconstrictors such as angiotensin II (ANG II) (Savin 1986; Scharschmidt et al 1986a). It is likely that mesangial cells mediate this mechanical activity, given their contractile phenotype and central location within the capillary loops, suited to application of radial forces (Latta 1973 ; Kreisberg et al 1985).…”

Subpressor infusions of angiotensin II alter glomerular binding, prostaglandin E2, and cyclic AMP production.

“…3 These effects are due to the loss of vasorelaxant eicosanoids and they parallel the decrease in basal surface area (see Table 4) and enhanced sensitivity and magnitude of the contractile response of isolated glomeruli following ANG II infusion (see Figure 2). Therefore, the effect of ANG II infusion on glomerular PGEj was evaluated.…”

“…3 Surface area was determined using an inverted Nikon microscope (Chiyoda-Ku, Japan) attached to a digitizing screen, as described in detail elsewhere. 3 Surface areas were determined for 30 to 50 glomeruli at each dose level of ANG II by a person other than the one who conducted the experiment. All samples were coded and measured blind to remove observer bias.…”

“…Enhanced in vitro responsiveness to ANG II has been reported by others and attributed to diminished in vitro eicosanoid biosynthesis, which would oppose mesangial cell contraction. 3 …”

“…A decrease in glomerular PGE^ has been documented previously to enhance ANG II-induced decrements in GSA, effects that are reversed by addition of exogenous PGEj. 3 Therefore, a decrease in glomerular PGEj could contribute to the pathophysiology. These findings seem at variance with reports that ANG II increases PGE^ production by mesangial cells.…”