Like many polypeptide hormones and zymogens, renin is synthesized in a prepro form that undergoes sequential processing to a prozymogen (prorenin) and then to the mature form of the enzyme. Prorenin, which is enzymatically inactive, constitutes the predominant species in plasma. Even more striking increases in prorenin levels are seen in patients with diabetes mellitus, often in association with or antecedent to diabetic microangiopathy. We confirmed these findings in two separate cohorts of diabetic patients and found that prorenin levels are also increased in the early stages of streptozotocin (STZ)-induced diabetes in the rat, a model also characterized by a reduction in glomerular angiotensin receptors. Although it has been suggested that the increased levels of prorenin in diabetics may be due to impaired conversion to active renin, no direct evidence has been offered in support of this hypothesis. Alternative hypotheses such as impaired feedback inhibition of prorenin secretion by angiotensin, abnormal post-translational processing, and/or delayed plasma clearance have never been tested experimentally. To further our understanding of the mechanisms underlying abnormalities of renin synthesis, processing, and secretion in diabetic humans and in the STZ- induced model of diabetes in the rat we will test the hypotheses that: feedback inhibition of prorenin secretion by angiotensin is abnormal in diabetics with high prorenin levels, by evaluating the response to chronic infusion of des-Asp1-angiotensin II; the increased level of prorenin is due to impaired prorenin catabolism, by comparing the rate of disappearance of 125I-labeled human recombinant prorenin in diabetics with and without increased prorenin levels and control subjects; the increased level of prorenin in the early stages of STZ-induced diabetes in the rat is due to extrarenal synthesis and/or altered post-translational processing, by determining renin gene expression in extrarenal tissues and the content of prorenin and active renin in renal juxtaglomerular cells; the decrease in renal angiotensin II binding sites in the diabetic rat results in impaired feedback inhibition of prorenin secretion, by measuring plasma levels of prorenin and active renin and renal angiotensin II receptor binding in response to angiotensin II, and angiotensin converting enzyme inhibitor, or angiotensin receptor antagonist; diabetes mellitus alters the plasma clearance and/or tissue distribution of prorenin by measuring the rate of disappearance of 125I-labeled recombinant rat prorenin from the circulation of normal and diabetic rats and characterizing the label renin species that appear in liver, kidney and other sites of catabolism.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL011046-27
Application #
2214654
Study Section
Cardiovascular and Renal Study Section (CVB)
Project Start
1977-01-01
Project End
1996-03-31
Budget Start
1994-04-01
Budget End
1996-03-31
Support Year
27
Fiscal Year
1994
Total Cost
Indirect Cost
Name
University of California San Francisco
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
073133571
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Giacchetti, G; Sechi, L A; Griffin, C A et al. (2000) The tissue renin-angiotensin system in rats with fructose-induced hypertension: overexpression of type 1 angiotensin II receptor in adipose tissue. J Hypertens 18:695-702
Engler, M M; Schambelan, M; Engler, M B et al. (1998) Effects of dietary gamma-linolenic acid on blood pressure and adrenal angiotensin receptors in hypertensive rats. Proc Soc Exp Biol Med 218:234-7
Sechi, L A; Ceriello, A; Griffin, C A et al. (1997) Renal antioxidant enzyme mRNA levels are increased in rats with experimental diabetes mellitus. Diabetologia 40:23-9
Griffin, C A; Giacchetti, G; Schambelan, M et al. (1997) Ontogenic expression of renal and hepatic angiotensin II receptor genes in the rat. Nephron 76:103-10
Sechi, L A; Griffin, C A; Zingaro, L et al. (1997) Effects of angiotensin II on insulin receptor binding and mRNA levels in normal and diabetic rats. Diabetologia 40:770-7
Valentin, J P; Sechi, L A; Griffin, C A et al. (1997) The renin-angiotensin system and compensatory renal hypertrophy in the rat. Am J Hypertens 10:397-402
Sechi, L A; Griffin, C A; Giacchetti, G et al. (1996) Tissue-specific regulation of type 1 angiotensin II receptor mRNA levels in the rat. Hypertension 28:403-8
Sechi, L A; Griffin, C A; Giacchetti, G et al. (1996) Abnormalities of insulin receptors in spontaneously hypertensive rats. Hypertension 27:955-61
Sechi, L A; Valentin, J P; Griffin, C A et al. (1995) Receptors for atrial natriuretic peptide are decreased in the kidney of rats with streptozotocin-induced diabetes mellitus. J Clin Invest 95:2451-7
Valentin, J P; Sechi, L A; Griffin, C A et al. (1994) [Gene expression of the renin-angiotensin system in compensatory renal hypertrophy secondary to contralateral nephrectomy] Arch Mal Coeur Vaiss 87:1115-7

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