Sustained hyperglycemia is closely associated with increased risk to develop nephropathy. We have previously reported alterations in the intrarenal oxygen metabolism already after the early onset of diabetes. Furthermore, formation of advanced glycation end-products (AGE) is postulated as a major contributor to diabetic nephropathy. We therefore investigated the possible relationship between altered oxygen metabolism and AGE in diabetic kidneys.
Normoglycemic and streptozotocin-diabetic rats with and without chronic treatment with aminoguanidine (AGE inhibitor; 600 mg/kg bw/24 h in drinking water) or L-N6-(1-Iminoethyl)lysine (L-NIL, iNOS inhibitor, 1 mg/kg bw/24 h in drinking water) were studied 2 weeks after induction of diabetes. Glomerular filtration rate (GFR) was estimated by inulin clearance, oxygen tension (pO2) and interstitial pH by microelectrodes and regional renal blood flow (RBF) by laser-Doppler. Histological changes were evaluated on fixed tissue.
Glomerular hyperfiltration was unaffected by aminoguanidine, whereas L-NIL normalized GFR in diabetic rats. pO2 and interstitial pH, but not RBF, were lower in both kidney cortex and medulla compared to control rats, but was unaffected by both chronic treatments. Urinary protein excretion was higher in diabetic rats and unaffected by L-NIL, whereas aminoguanidine paradoxically increased this parameter. Damage scores were similar in all groups.
In conclusion, diabetes-induced alterations in intrarenal oxygen metabolism are independent of the AGE pathway, and precede any morphological changes. These findings highlight the early stage of diabetes as being a metabolic disorder also in the kidney.
AGE Diabetes Kidney Oxygen tension
This is a preview of subscription content, log in to check access.
This study was supported by the Swedish Medical Research Council (10840), The Swedish Society for Medical Research, The Magnus Bergvall Foundation and NIH K99/R00 grant (DK077858).
Schjoedt KJ, Hansen HP, Tarnow L et al (2008) Long-term prevention of diabetic nephropathy: an audit. Diabetologia 51:956–961CrossRefGoogle Scholar
The Diabetes Control and Complications Trial Research Group (1993) The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med 329:977–986CrossRefGoogle Scholar
Yip JW, Jones SL, Wiseman MJ et al (1996) Glomerular hyperfiltration in the prediction of nephropathy in IDDM: a 10-year follow-up study. Diabetes 45:1729–1733CrossRefGoogle Scholar
Palm F, Cederberg J, Hansell P et al (2003) Reactive oxygen species cause diabetes-induced decrease in renal oxygen tension. Diabetologia 46:1153–1160CrossRefGoogle Scholar
Palm F, Hansell P, Ronquist G et al (2004) Polyol-pathway-dependent disturbances in renal medullary metabolism in experimental insulin-deficient diabetes mellitus in rats. Diabetologia 47:1223–1231CrossRefGoogle Scholar
Miyata T, de Strihou CY (2010) Diabetic nephropathy: a disorder of oxygen metabolism? Nat Rev Nephrol 6:83–95CrossRefGoogle Scholar
Nishikawa T, Edelstein D, Du XL et al (2000) Normalizing mitochondrial superoxide production blocks three pathways of hyperglycaemic damage. Nature 404:787–790CrossRefGoogle Scholar
He C, Sabol J, Mitsuhashi T et al (1999) Dietary glycotoxins: inhibition of reactive products by aminoguanidine facilitates renal clearance and reduces tissue sequestration. Diabetes 48:1308–1315CrossRefGoogle Scholar
Inagi R, Yamamoto Y, Nangaku M et al (2006) A severe diabetic nephropathy model with early development of nodule-like lesions induced by megsin overexpression in RAGE/iNOS transgenic mice. Diabetes 55:356–366CrossRefPubMedGoogle Scholar
Kern TS, Engerman RL (2001) Pharmacological inhibition of diabetic retinopathy: aminoguanidine and aspirin. Diabetes 50:1636–1642CrossRefGoogle Scholar
Wilkinson-Berka JL, Kelly DJ, Koerner SM et al (2002) ALT-946 and aminoguanidine, inhibitors of advanced glycation, improve severe nephropathy in the diabetic transgenic (mREN-2)27 rat. Diabetes 51:3283–3289CrossRefGoogle Scholar
Junqueira LC, Bignolas G, Brentani RR (1979) Picrosirius staining plus polarization microscopy, a specific method for collagen detection in tissue sections. Histochem J 11:447–455CrossRefGoogle Scholar
Pulido JS (1996) Experimental nonenzymatic glycosylation of vitreous collagens occurs by two pathways. Trans Am Ophthalmol Soc 94:1029–1072PubMedPubMedCentralGoogle Scholar
Brownlee M (1992) Glycation products and the pathogenesis of diabetic complications. Diabetes Care 15:1835–1843CrossRefGoogle Scholar
Kelly DJ, Gilbert RE, Cox AJ et al (2001) Aminoguanidine ameliorates overexpression of prosclerotic growth factors and collagen deposition in experimental diabetic nephropathy. J Am Soc Nephrol 12:2098–2107PubMedPubMedCentralGoogle Scholar
Mitsuhashi T, Nakayama H, Itoh T et al (1993) Immunochemical detection of advanced glycation end products in renal cortex from STZ-induced diabetic rat. Diabetes 42:826–832CrossRefPubMedPubMedCentralGoogle Scholar
Rosca MG, Mustata TG, Kinter MT et al (2005) Glycation of mitochondrial proteins from diabetic rat kidney is associated with excess superoxide formation. Am J Physiol Renal Physiol 289:F420–430CrossRefPubMedPubMedCentralGoogle Scholar
Miyata T, Izuhara Y (2008) Inhibition of advanced glycation end products: an implicit goal in clinical medicine for the treatment of diabetic nephropathy? Ann New York Acad Sci 1126:141–146CrossRefGoogle Scholar
Bolton WK, Cattran DC, Williams ME et al (2004) Randomized trial of an inhibitor of formation of advanced glycation end products in diabetic nephropathy. Am J Nephrol 24:32–40CrossRefPubMedGoogle Scholar
Bank N, Aynedjian HS (1993) Role of EDRF (nitric oxide) in diabetic renal hyperfiltration. Kidney Int 43:1306–1312CrossRefPubMedGoogle Scholar
Noh H, Ha H, Yu MR et al (2002) High glucose increases inducible NO production in cultured rat mesangial cells. Possible role in fibronectin production. Nephron 90:78–85CrossRefPubMedGoogle Scholar
Veelken R, Hilgers KF, Hartner A et al (2000) Nitric oxide synthase isoforms and glomerular hyperfiltration in early diabetic nephropathy. J Am Soc Nephrol 11:71–79PubMedGoogle Scholar
Schwartz D, Schwartz IF, Blantz RC (2001) An analysis of renal nitric oxide contribution to hyperfiltration in diabetic rats. J Lab Clin Med 137:107–114CrossRefPubMedGoogle Scholar
Zhao Z, Zhao C, Zhang XH et al (2009) Advanced glycation end products inhibit glucose-stimulated insulin secretion through nitric oxide-dependent inhibition of cytochrome c oxidase and adenosine triphosphate synthesis. Endocrinology 150:2569–2576CrossRefPubMedPubMedCentralGoogle Scholar
Bai-Feng L, Yong-Feng L, Ying C (2010) Silencing inducible nitric oxide synthase protects rat pancreatic islet. Diabetes Res Clin Pract 89:268–275CrossRefPubMedGoogle Scholar