|ISSN No. 1606-7754 Vol.16 No.2 August 2008|
The association of TGF-β1, angiotensin II and oxidative stress with diabetic nephropathy in type 2 diabetic patients
HO El-mesallamy1, MZ Gad2 and AM Sallam1
Department of Biochemistry, Faculty of Pharmacy, Ain Shams University1, Department of Biochemistry, Faculty of Pharmacy, The German University of Cairo2, Cairo, Egypt
Diabetic nephropathy (DN) is a severe complication of diabetes which may progress to end-stage renal disease (ESRD). Chronic hyperglycemia is considered as the major initiator of DN, either by creation of oxidative stress or by induction of growth factors and cytokines. Moreover, dyslipidemia plays a role in DN progression. The aim of our study was to examine the changes in lipid profile, malondialdehyde (MDA), transforming growth factor-β1 (TGF-β1) and angiotensin II (Ang II) levels in type 2 diabetic patients associated with kidney disease. Diabetic microalbuminuric (n=25) and macroalbuminuric (n=15) patients showed significantly higher levels of blood glucose, glycated hemoglobin (HbA1c), triglycerides (TG), total cholesterol (TC), MDA, TGF-β1 and Ang II than either diabetic normoalbuminuric (n=14) or control (n=16) subjects. In the microalbuminuric and macroalbuminuric diabetic groups, albumin excretion rate (AER) was positively correlated with MDA (r=0.448, p<0.01), TGF-β1 (r=0.81, p<0.01) and Ang II (r=0.772, p<0.01). Additionally, MDA correlated with TGF-β1 (r=0.625, p<0.01) and Ang II (r=0.428, p<0.01). In conclusion, dyslipidemia, oxidative stress, and increased TGF-β1 and Ang II are associated with DN in type 2 diabetic patients.
Keywords: angiotensin II, oxidative Stress, diabetic patients
The incidence of diabetes mellitus (DM) is rapidly increasing and already affects a large number of subjects all over the world, with an incidence expected to increase to over 200 million by 2010.1 Diabetes is a leading cause of mortality and morbidity largely due to its micro and macrovascular complications. Microvascular complications include retinopathy and nephropathy while macrovascular complications include coronary artery disease and cerebrovascular disease.2
Diabetic nephropathy (DN) is one of the most severe complications of DM. Although the progression of DN is very slow, many diabetic patients develop end-stage renal disease (ESRD) and require hemodialysis therapy.3 Clinically incipient nephropathy is first manifested as persistent microalbuminuria. Subsequently, the onset of overt DN is heralded by the appearance of persistent proteinuria.4
Chronic hyperglycemia is considered as the major initiator of diabetic kidney disease.5 One proposed mechanism is that hyperglycemia creates a state of oxidative stress both by generating free radicals and attenuating antioxidant mechanisms.6 This oxidative stress causes cellular injury and tissue damage by promoting several reactions such as lipid peroxidation.7 Malondialdehyde (MDA), a product of lipid peroxidation is increased in the serum of DM patients.8
Another postulated mechanism is that hyperglycemia induces a number of growth factors and cytokines in the kidney.9 Of these, transforming growth factor- β1 (TGF-β1) represents the central player in the fibrogenic process because it causes extracellular matrix (ECM) production and inhibits its degradation. Moreover, the experimental use of TGF-β1 neutralizing antibodies prevented glomerular enlargement and increase in renal cell mass.10 ECM accumulation and renal cell hypertrophy are the most prominent hallmarks of diabetic kidney disease.11
Angiotensin II (Ang II), a vasoactive peptide, is a potent stimulus for TGF-β1 production by the kidney. It acts in synergy with elevated glucose concentration to stimulate matrix production.12
Besides hyperglycemia, diabetic dyslipidemia plays an important role in the progression of DN. Diabetic nephropathy per se, in addition to diabetes, impairs lipid metabolism.13 The aim of the present study was to examine the changes in lipid profile, MDA, TGF-β1 and Ang II levels in type 2 diabetic patients associated with kidney disease.