Effect of inhibiting renal kallikrein on prostaglandin E2, water, and sodium excretion.
To test the hypothesis that renal kinins act as natriuretic and diuretic hormones, we examined the effect of inhibiting glandular kallikrein on renal function in normotensive unanesthetized rats during normal sodium intake. To inhibit kallikrein at both the luminal and basolateral sides of the distal nephron, we used Fab fragments of monoclonal antibodies to rat urinary kallikrein (Fab-kallikrein). Fab fragments have advantages over intact IgG: they are filtered through the glomerulus and reach the lumen of the distal nephron, where kallikrein is localized and urinary kinins are released. Furthermore, the Fab fragment-antigen complex does not activate the complement system, avoiding the side effects associated with intact antibodies. Fab-kallikrein effectively blocked generation of kinins in the nephron lumen, decreasing urinary kininogenase activity (kallikrein) by 74% to 85% and kinin excretion by 76% to 79%. Fab-kallikrein induced a 30% decrease in urine volume and a 20% to 40% decrease in urinary sodium excretion but did not alter blood pressure, glomerular filtration rate, or renal blood flow. Although urinary prostaglandin E2 excretion also tended to decrease, this change was slower and of lesser magnitude than those of kinin and kininogenase excretion and did not attain statistical significance after Bonferroni's correction. In controls injected with either vehicle or Fab fragments of monoclonal antibodies to ricin (a vegetable protein not present in mammals), none of these parameters decreased significantly. We conclude that renal kinins participate in the short-term regulation of water and sodium excretion in normotensive unanesthetized rats, acting as diuretic and natriuretic hormones.(ABSTRACT TRUNCATED AT 250 WORDS)
Saitoh
S
S
Department of Medicine, Henry Ford Hospital, Detroit, MI 48202-2689, USA.
Scicli
A G
AG
Peterson
E
E
Carretero
O A
OA
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D001834:Body Water / Q000378:metabolism*; D015232:Dinoprostone / Q000652:urine*; D007140:Immunoglobulin Fab Fragments / Q000276:immunology; D007610:Kallikreins / Q000037:antagonists & inhibitors / Q000502:physiology*; D007668:Kidney / Q000502:physiology*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D012964:Sodium / Q000652:urine*
D000911:Antibodies, Monoclonal; D007140:Immunoglobulin Fab Fragments; D012964:Sodium; D007610:Kallikreins; D015232:Dinoprostone