Summary
One of the characteristics of early diabetic nephropathy is glomerular hyperfiltration and hyperperfusion. Many factors have been suggested to induce glomerular hyperperfusion among which are an increased production of vasodilatory prostanoids, an increased synthesis of nitric oxide, a reduced responsiveness of afferent glomerular arterioles to vasoconstrictor stimuli due to diabetic metabolic disturbances and a decreased receptor density for angiotensin II. It has been known for years that angiotensin II is formed locally due to the local activation of the renin angiotensin system. The local angiotensin II concentration, however, is not only regulated by the synthesis rate but also by the local degradation through activation of an aminopeptidase. The main finding of the present study was that the mRNA expression and activity of the angiotensin II degrading enzyme, angiotensinase A, was increased twofold in diabetic rats at 5 weeks and that the increase in mRNA expression was suppressed by insulin therapy and short-term treatment with the angiotensin II antagonist saralasin, whereas angiotensinase A enzyme activity was only reduced by saralasin and not by insulin. These results demonstrate that the angiotensin II degrading exopeptidase angiotensinase A is activated in diabetic glomeruli. This increased activity may be an additional mechanism to explain glomerular hyperfiltration and hyperperfusion in early diabetic nephropathy.
Similar content being viewed by others
Abbreviations
- ATA:
-
Angiotensinase A
- STZ:
-
streptozotocin
- PRA:
-
plasma renin activity
- RAS:
-
renin angiotensin system
- AII:
-
angiotensin II
- Sar:
-
saralasin
- Val:
-
valine
- Ala:
-
alanine
References
Bank N (1991) Mechanisms of diabetic hyperfiltration. Kidney Int 40: 792–807
Ichikawa I, Harris RC (1991) Angiotensin actions in the kidney: renewed insights into the old hormone. Kidney Int 40: 583–596
Ingelfinger JR, Dzau VJ (1991) Molecular biology of renal injury: emphasis on the role of the renin-angiotensin system. J Am Soc Nephrol 2:S9-S20
Anderson S, Jung FF, Ingelfinger JR (1993) Renal reninangiotensin system in diabetes: functional, immunohistochemical, and molecular biological correlations. Am J Physiol 265:F477-F486
Correa-Rotter R, Hostetter TH, Rosenberg ME (1992) Renin and angiotensinogen gene expression in experimental diabetes mellitus. Kidney Int 41: 796–804
Everett AD, Scott J, Wilfong N et al. (1992) Renin and angiotensinogen expression during the evolution of diabetes. Hypertension 19: 70–78
Glenner GG, McMillan PJ, Flok JE (1962) A mammalian peptidase specific for the hydrolysis of N-terminal α-l-glutamyl and aspartyl residues. Nature 194: 867–869
Kugler P, Wolf G, Scherberich H (1985) Histochemical demonstration of peptidases in the human kidney. Histochemistry 83: 337–341
Wolf G, Thaiss F, Scherberich JE, Schoeppe W, Stahl RAK (1990) Glomerular angiotensinase A in the rat: increase of enzyme activity following renal ablation. Kidney Int 38: 862–868
Wolf G, Thaiss F, Müller E et al. (1995) Glomerular mRNA expression of angiotensinase A after renal ablation. Exp Nephrol 3: 240–248
Thaiss F, Germann PJ, Kudelka S, Schoeppe W, Helmchen U, Stahl RAK (1989) The effect of thromboxane synthesis inhibition on renal function in a model of membranous nephropathy. Kidney Int 35: 76–83
Stahl RAK, Helmchen U, Paravicini M, Ritter LJ, Schollmeyer P (1984) Glomerular prostaglandin formation in two-kidney, one clip hypertensive rats. Am J Physiol 247:F975-F981
Hsueh WA (1992) Effect of the renin-angiotensin system in the vascular disease of type II diabetes mellitus. Am J Med 92:S13-S19
Björck S (1990) The renin angiotensin system in diabetes mellitus. A physiological and therapeutic study. Scand J Urol Nephrol 126[Suppl]:1–51
Wolf G, Neilson EG (1993) Angiotensin II as a renal growth factor. J Am Soc Nephrol 3: 1531–1540
Rosenberg ME, Smith LJ, Correa-Rotter R, Hostetter TH (1994) The paradox of the renin-angiotensin system in chronic renal disease. Kidney Int 45: 403–410
Kalinyak JE, Sechi LA, Griffin CA et al. (1993) The reninangiotensin system in streptozotocin-induced diabetes mellitus in the rat. J Am Soc Nephrol 4: 1337–1345
Ballermann BJ, Skorecki KL, Brenner BM (1984) Reduced glomerular angiotensin II receptor density in early untreated diabetes mellitus in the rat. Am J Physiol 247:F110-F116
Wilkes BM (1987) Reduced glomerular angiotensin II receptor density in diabetes mellitus in the rat: time course and mechanism. Endocrinology 120: 1293–1298
Cheng HF, Burns KV, Harris RC (1994) Reduced proximal tubule angiotensin II receptor expression on streptozotozin-induced diabetes mellitus. Kidney Int 46: 1603–1610
Erdös EG, Skidgel RA (1990) Renal metabolism of angiotensin I and II. Kidney Int 38:S24-S27
Wang J, Cooper MD (1993) Histidine residue in the zinc-binding motif of aminopeptidase A is critical for enzyme activity. Proc Natl Acad Sci USA 90: 1222–1226
Wu Q, Li L, Cooper MD, Pierres M, Gorvel JP (1991) Aminopeptidase A activity of the murine B-lymphocyte differentiation antigen BP-1/6C3. Proc Natl Acad Sci USA 88: 676–680
Johnson RJ, Alpers CE, Yoshimura A et al. (1992) Renal injury from angiotensin II-mediated hypertension. Hypertension 19: 464–474
Larkins RG, Dunlop ME (1992) The link between hyperglycemia and diabetic nephropathy. Diabetologia 35: 499–504
Tesfamariam B, Brown ML, Cohen RA (1991) Elevated glucose impairs endothelium-dependent relaxation by activating protein kinase C. J Clin Invest 87: 1643–1648
DeRubertis FR, Craven PA (1993) Eicosanoids in the pathogenesis of the functional and structural alterations of the kidney in diabetes. Am J Kid Dis 22: 727–735
Stefanovic V, Vlahovic P, Ardaillou N, Ronco P, Ardaillou R (1992) Cell surface aminopeptidase A and N activities in human glomeular epithelial cells. Kidney Int 41: 1571–1580
Wilkes BM, Mento PF, Vernace MA (1993) Angiotensin responsiveness in hyperfiltering and nonhyperfiltering diabetic rats. J Am Soc Nephrol 4: 1346–1353
Wilkes BM, Vernace MA, Mento PF, Maita ME, Hollander AM (1993) Increased metabolic clearance rate of angiotensin II in diabetic rats is due to renal mechanism(s). J Am Soc Nephrol 4: 808 (Abstract)
Rosenberg ME, Correa-Rotter R, Inagami T, Kren SM, Hostetter TH (1991) Glomerular renin synthesis and storage in the remnant kidney in the rat. Kidney Int 40: 677–683
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Thaiss, F., Wolf, G., Assad, N. et al. Angiotensinase A gene expression and enzyme activity in isolated glomeruli of diabetic rats. Diabetologia 39, 275–280 (1996). https://doi.org/10.1007/BF00418342
Received:
Revised:
Issue Date:
DOI: https://doi.org/10.1007/BF00418342