Renin-angiotensin system activation and interstitial inflammation in human diabetic nephropathy (original) (raw)
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Role of the renin angiotensin system in diabetic nephropathy
World Journal of Diabetes, 2010
1 Ziyadeh FN. Renal tubular basement membrane and collagen type IV in diabetes mellitus. Kidney Int 1993; 43: 114-120 2 Lewis EJ, Hunsicker LG, Bain RP, Rohde RD. The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy. The Collaborative Study Group. N Engl J Med 1993; Breitbart RE, Acton S. A novel angiotensin-converting enzyme-related carboxypeptidase (ACE2) converts angiotensin I to angiotensin 1-9. Circ Res 2000; 87: E1-E9 9 Tipnis SR, Hooper NM, Hyde R, Karran E, Christie G, Turner AJ. A human homolog of angiotensin-converting enzyme. Cloning and functional expression as a captopril-insensitive carboxypeptidase. J Biol Chem 2000; 275: 33238-33243 10 Zatz R, Dunn BR, Meyer TW, Anderson S, Rennke HG, Brenner BM. Prevention of diabetic glomerulopathy by pharmacological amelioration of glomerular capillary hypertension. J Clin Invest 1986; 77: 1925-1930 11 Shiota A, Yamamoto K, Ohishi M, Tatara Y, Ohnishi M, Maekawa Y, Iwamoto Y, Takeda M, Rakugi H. Loss of ACE2 accelerates time-dependent glomerular and tubulointerstitial damage in streptozotocin-induced diabetic mice. Hypertens Res 2010; 33: 298-307 12 Gilbert RE, Cox A, Wu LL, Allen TJ, Hulthen UL, Jerums G, Cooper ME. Expression of transforming growth factor-beta1 and type IV collagen in the renal tubulointerstitium in experimental diabetes: effects of ACE inhibition. Diabetes 1998; 47: 414-422 13 Wolf G, Mueller E, Stahl RA, Ziyadeh FN. Angiotensin IIinduced hypertrophy of cultured murine proximal tubular cells is mediated by endogenous transforming growth factorbeta. J Clin Invest 1993; 92: 1366-1372 14 Kalinyak JE, Sechi LA, Griffin CA, Don BR, Tavangar K, Kraemer FB, Hoffman AR, Schambelan M. The renin-angiotensin system in streptozotocin-induced diabetes mellitus in the rat. J Am Soc Nephrol 1993; 4: 1337-1345 15 Tesch GH. MCP-1/CCL2: a new diagnostic marker and therapeutic target for progressive renal injury in diabetic nephropathy. Am J Physiol Renal Physiol 2008; 294: F697-F701
Journal of Pharmacological Sciences, 2012
Urinary excretion of albumin (UAlb) is used clinically as a marker of diabetic nephropathy (DN). Although DN was thought to be a unidirectional process, recent studies demonstrated that a large proportion of patients diagnosed with DN reverted to normoalbuminuria. Moreover, despite the normoalbuminuria, one-third of them exhibited reduced renal function even during the microalbuminuric stage. This study was performed to investigate whether urinary angiotensinogen (UAGT) level may serve as a useful marker of the early stage of experimental type 1 diabetes (T1DM). T1DM was induced by a single intraperitoneal injection of streptozotocin. Control mice were injected with citrate buffer. Two days after streptozotocin injection, half of the mice received continuous insulin treatment. Our data showed that UAlb excretion was increased 6 days after streptozotocin injection compared to controls, whereas UAGT excretion was increased at an earlier time point. These increases were reversed by insulin treatment. The UAGT to UAlb ratio was increased in diabetic mice compared to control mice. Furthermore, the increased AGT expression in the kidneys was observed in diabetic mice. These data suggest that UAGT might be useful as a novel early biomarker of activation of the renin-angiotensin system in experimental type 1 diabetes.
Renin-angiotensin system may trigger kidney damage in NOD mice
Journal of The Renin-angiotensin-aldosterone System, 2010
Diabetic nephropathy is a complication of diabetes and one of the main causes of end-stage renal disease. A possible causal link between renin-angiotensin aldosterone system (RAAS) and diabetes is widely recognized but the mechanisms by which the RAAS may lead to this complication remains unclear. The aim of this study was to evaluate angiotensin-I converting enzyme (ACE) activity and expression in numerous tissues, especially kidney, of non-obese diabetic mouse. Kidney, lung, pancreas, heart, liver and adrenal tissues from diabetic and control female NOD mice were homogenized for measurement of ACE activity, SDS-PAGE and Western blotting for ACE and ACE2, immunohistochemistry for ACE and angiotensins I, II and 1-7 and bradykinin quantification. ACE activity was higher in kidney, lung and adrenal tissue of diabetic mice compared with control mice. In pancreas, activity was decreased in the diabetic group. Western blotting analysis indicated that both groups presented ACE isoforms with molecular weights of 142 and 69 kDa and a decrease in ACE2 protein expression. Angiotensin concentrations were not altered within groups, although bradykinin levels were higher in diabetic mice. The immunohistochemical study in kidney showed an increase in tubular ACE expression. Our results show that the RAAS is affected by diabetes and the elevated ACE/ACE2 ratio may contribute to renal damage.
Renin and angiotensinogen gene expression in experimental diabetes mellitus
Kidney International, 1992
Renin and angiotensinogen gene expression in experimental diabetes mellitus. The renin-angiotensin system may play a role in the initiation and progression of diabetic kidney disease. In this study, the local intrarenal renin-angiotensin system was examined in streptozotocintreated rats maintained moderately hyperglycemic by daily low-dose insulin injection. Four weeks after induction of diabetes, plasma renin activity was significantly lower in the diabetic compared to a nondiabetic control group (diabetes: 2.30 0.30 vs. control: 6.93 1.36 ng Al/ml/hr; P < 0.01). Renal tissue renin content (diabetes: 1.81 0.46 vs. control: 2.05 0.27 Lg Al/mg protein/hr; P < 0.05) and renal renin mRNA (diabetes: 2.32 0.16 vs. control: 1.89 0.12 pg/Lg RNA; P = NS) were not different between diabetic and control rats. Renal and liver angiotensinogen mRNA were lower in the diabetic group. Glomerular renin mRNA was not different between the diabetic and sham group. The dissociation between systemic renin activity (a decrease), and in renal renin content or mRNA in the diabetic rats (no change), suggests a post-translational alteration in renin processing and/or renin secretion.
NF-kappa B activation and overexpression of regulated genes in human diabetic nephropathy
Nephrology Dialysis Transplantation, 2004
Background. Nuclear factor-kB (NF-kB) regulates genes involved in renal disease progression, such as the chemokines monocyte chemoattractant protein-1 (MCP-1) and RANTES. NF-kB is activated in experimental models of renal injury, and in vitro studies also suggest that proteinuria and angiotensin II could be important NF-kB activators. It has been proposed that locally produced MCP-1 may be involved in the development of diabetic nephropathy (DN). We examined the hypothesis that NF-kB could be an indicator of renal damage progression in DN. Methods. Biopsy specimens from 11 patients with type 2 diabeties and overt nephropathy were studied by southwestern histochemistry for the in situ detection of activated NF-kB. In addition, by immunohistochemistry and/or in situ hybridization, we studied the expression of MCP-1 and RANTES, whose genes are regulated by NF-kB. Results. NF-kB was detected mainly in cortical tubular epithelial cells and, to a lesser extent, in some glomerular and interstitial cells. A strong upregulation of MCP-1 and RANTES was observed in all the cases, mainly in tubular cells, and there was a strong correlation between the expression of these chemokines and NF-kB activation in the same cells, as observed in serial sections (r ¼ 0.7; P ¼ 0.01). In addition, the tubular expression of these chemokines was correlated mainly with the magnitude of the proteinuria (P ¼ 0.002) and with interstitial cell infiltration (P<0.05).
Urinary angiotensinogen as a potential biomarker of diabetic nephropathy
Clinical kidney journal, 2014
Activation of the renin-angiotensin-aldosterone system (RAAS) is an important mediator of diabetic nephropathy. Urinary angiotensinogen, a novel biomarker of the intrarenal RAAS, is associated with progressive kidney injury. In this study, the authors investigated the determinants of urinary angiotensinogen and its associations with staging of diabetic nephropathy. Random urine samples were collected from the patients with type 2 diabetes with normoalbuminuria (n = 52), microalbuminuria (n = 52) and macroalbuminuria (n = 51) for the measurement of angiotensinogen by sensitive and specific ELISAs. Control samples were collected from healthy volunteers (n = 20) who had normal albuminuria and renal function. Urinary angiotensinogen was higher in microalbuminuric and macroalbuminuric diabetes than in controls [63.44 (interquartile range, IQR: 22.08, 174.8) versus 398.38 (IQR: 205.03, 673.68) versus 9.12 (IQR: 3.76, 23.82) ng/mg creatinine, respectively, P < 0.001]. In diabetes with n...
Anti-Inflammatory Therapy Modulates Nrf2-Keap1 in Kidney from Rats with Diabetes
Oxidative Medicine and Cellular Longevity, 2016
This study addressed the relationship of proinflammatory cytokines and Nrf2-Keap1 system in diabetic nephropathy. The experimental groups were control, diabetic, and diabetic treated with mycophenolate mofetil (MMF). The renal function, proinflammatory and profibrotic cytokines, oxidative stress, morphology, and nephrin expression were assessed. Diabetic group showed impaired renal function in association with oxidative stress and decreased Nrf2 nuclear translocation. These results were associated with increased mesangial matrix index, interstitial fibrosis, and increased nephrin expression in cortex and urine excretion. Additionally, interleukin-1β, IL-6, and transforming growth factor-β1 were increased in plasma and kidney. MMF treatment conserved renal function, prevented renal structural alterations, and partially prevented the proinflammatory and profibrotic cytokines overexpression. Despite that MMF treatment induced nephrin overexpression in renal tissue, preventing its urina...
Journal of the renin-angiotensin-aldosterone system : JRAAS
The renin-angiotensin system and epithelial-mesenchymal transition play crucial roles in the development of kidney fibrosis. The connection between the renin-angiotensin system and transforming growth factor-β in epithelial-mesenchymal transition remains largely unknown. We assessed oxidative stress, cytokine levels, renal morphology, profibrotic growth factor and renin-angiotensin system component expression, and cell-specific E- and N-cadherin expression in the kidneys of gerbils with streptozotocin-induced diabetes mellitus. Animals in the experimental group received an intraperitoneal injection of streptozotocin to induce diabetes. The diabetic gerbil kidneys presented kidney injury, which was manifested as distorted glomeruli, necrosis of tubular cells, dilated tubular lumen, and brush border loss. Additionally, the diabetic gerbil kidneys exhibited significantly higher expressions of 8-hydroxy-2'-deoxyguanosine, nuclear factor-kB, toll-like receptor 4, tumor necrosis facto...
Role of Inflammation in the Pathogenesis of Diabetic Nephropathy
Diabetic nephropathy is the major microvascular complication of diabetes mellitus and remains the leading cause of increased morbidity and mortality for diabetic patients. Recent evidence suggests that chronic subclinical inflammation is a key pathogenetic mechanism of the disease. Pro inflammatory cytokines and particularly tumor necrosis factor and its receptors appear to play a major role in the process and are emerging novel biomarkers of the development and progression of diabetic nephopathy. Moreover, manipulation of the TNF superfamily system will hopefully provide a new therapeutic option for the disease. Keywords: C-Reactive Protein; Diabetes Mellitus; Diabetic Nephropathy; Inflammation; Tumor Necrosis Factor-a; Tumor Necrosis Factor Receptors.