Sex dependent differences in renal angiotensinogen as an early marker of diabetic nephropathy

AIM: The renal renin-angiotensin system (RAS) has been implicated in the pathogenesis of diabetic nephropathy. The aim of this study was to investigate sex differences in renal renin-angiotensin system (RAS) and the roles of androgens in diabetes-associated renal injury. METHODS: Renal injury and fibrosis was studied in streptozotocin-induced diabetic rats by albuminuria and by gene expression of collagen-I and fibronectin. RAS was investigated by analyzing the plasma angiotensinogen (AOGEN) and renin activity (PRA) and their renal gene expression. Also, a group of diabetic rats was treated with the antiandrogen flutamide. RESULTS: Albuminuria was significantly lower in diabetic females than in males (1.2 [0.8-1.5] vs. 4.4 [2.2-6.1] mg/24h, data are median [IQR] values, p0.05), as were collagen-I and fibronectin mRNAs. Furthermore, AOGEN mRNA levels were strongly correlated with albuminuria (Spearman r = 0.64, 95%[CI] 0.36 to 0.81, p< 0.0001). Diabetes decreased PRA, renal renin mRNA and plasma AOGEN in both females and males. Antiandrogen treatment decreased albuminuria only in diabetic males without affecting the endocrine or renal RAS. CONCLUSIONS: These data indicate that renal but not hepatic AOGEN or renin is positively associated with diabetic albuminuria and contribute to the sex-dependent differences in renal injury. Androgens may contribute to albuminuria in male independently of the RAS

Type 1 diabetes mellitus induces structural changes and molecular remodelling in the rat kidney

There is much evidence that diabetes mellitus (DM) –induced hyperglycemia (HG) is responsible for kidney failure or nephropathy leading to cardiovascular complications. Cellular and molecular mechanism(s) whereby DM can damage the kidney is still not fully understood. This study investigated the effect of streptozotocin (STZ)-induced diabetes (T1DM) on the structure and associated molecular alterations of the isolated rat left kidney following 2 and 4 months of the disorder compared to the respective age-matched controls. The results revealed hypertrophy and general disorganized architecture of the kidney characterized by expansion in glomerular borders, tubular atrophy and increased vacuolization of renal tubular epithelial cells in the diabetic groups compared to controls. Electron microscopic analysis revealed ultrastructural alterations in the left kidney highlighted by an increase in glomerular basement membrane width. In addition, increased caspase-3 immuno-reactivity was observed in the kidney of T1DM animals compared to age-matched controls. These structural changes were associated with elevated extracellular matrix (ECM) deposition and consequently, altered gene expression profile of ECM key components, together with elevated levels of key mediators (MMP9, integrin 5α, TIMP4, CTGF, vimentin) and reduced expressions of Cx43 and MMP2 of the ECM. Marked hypertrophy of the kidney was highlighted by increased atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) gene expression. These changes also correlated with increased TGFβ1 activity, gene expression in the left kidney and elevated active TGFβ1 in plasma of T1DM rats compared to control. The results clearly demonstrated that TIDM could elicit severe structural changes and alteration in biochemical markers (remodeling) in the kidney leading to diabetic nephropathy (DN)

Mechanisms of antioxidant and pro-oxidant effects of α-lipoic acid in the diabetic and nondiabetic kidney

Background. α-Lipoic acid is a potent antioxidant that improves renal function in diabetes by lowering glycemia, however, the mechanisms by which α-lipoic acid exerts its antioxidant effects are not completely understood. Methods. Metabolic parameters, renal function, and morphology, nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity and subunit expression were analyzed in nondiabetic and streptozotocin-induced diabetic rats fed normal rat chow (control) with or without α-lipoic acid (30 mg/kg body weight) for 12 weeks. Results. Blood glucose was increased with diabetes (nondiabetic + control 89 ± 3 mg/dL and diabetic + control 336 ± 28 mg/dL) and was similar with α-lipoic acid treatment (diabetic + α-lipoic acid 351 ± 14 mg/dL). In contrast, α-lipoic acid attenuated albuminuria (nondiabetic + control 8.9 ± 1.3 mg/day; diabetic + control 28.1 ± 4.6 mg/day; and diabetic + α-lipoic acid 17.8 ± 1.2 mg/day) associated with diabetes. Similarly, α-lipoic acid attenuated glomerulosclerosis (nondiabetic + control 0.22 ± 0.01; diabetic + control 0.55 ± 0.04; diabetic + α-lipoic acid 0.36 ± 0.03), tubulointerstitial fibrosis (nondiabetic + control 0.42 ± 0.18; diabetic + control 1.52 ± 0.05; diabetic + α-lipoic acid 1.10 ± 0.05), superoxide anion (O2-) generation (nondiabetic + control 15.8 ± 1.7; diabetic + control 87.1 ± 3.5; diabetic + α-lipoic acid 25.5 ± 3.3 RLU/mg protein), and urine 8-isoprostane (8-iso) excretion (nondiabetic + control 7.4 ± 1.4; diabetic + control 26.0 ± 4.5; diabetic + α-lipoic acid 19.6 ± 5.6 ng/day) associated with diabetes. α-Lipoic acid also reduced kidney expression of NADPH oxidase subunits p22phox and p47phox. Surprisingly, α-lipoic acid appears to cause pro-oxidant effects in nondiabetic animals, resulting in increased albuminuria (nondiabetic + α-lipoic acid 14.2 ± 1.2 mg/day), increase in plasma creatinine levels (nondiabetic + control 59 ± 6; diabetic + control 68 ± 6; nondiabetic + α-lipoic acid 86 ± 9; diabetic + α-lipoic acid 69 ± 7 μmol/L), exacerbated glomerulosclerosis and tubulointerstitial fibrosis, increased O2- generation, up-regulated p22phox and p47phox expression and increased 8-iso excretion. Conclusion. We conclude that α-lipoic acid improves albuminuria and pathology in diabetes by reducing oxidative stress, while in healthy animals, α-lipoic acid may act as a pro-oxidant, contributing to renal dysfunction. © 2005 by the International Society of Nephrology

Hormone replacement therapy, renal function and heart ultrasonographic parameters in postmenopausal women: an observational study

A certain degree of impaired kidney function is related to an increased cardiovascular risk. The cardiovascular protection exerted in the postmenopausal state by the hormone replacement therapy (HRT) is debated. No studies have so far explored the relationship between menopause, renal function and cardiovascular risk profile in healthy menopausal women in relation with HRT.A total of 362 postmenopausal healthy women with normal albumin excretion rate were recruited and divided into two groups (HRT+ and HRT-) according to the presence or absence of HRT. All participants underwent a complete routine biochemical analyses and an echocardiogram.Clinical characteristics of the two groups were similar, but HRT+ showed a significantly higher estimated glomerular filtration rate (GFR; by CKD-EPI formula). Regarding the heart ultrasonography, HRT+ had a significantly lower size of the aortic root and left atrium diameter (p = 0.038 and p = 0.012, respectively); no differences were found in the ejection fraction and Left Ventricular Mass Index (LVMI). In the whole study group, eGFR correlated inversely with LVMI and with the size of the aortic root (both p0.0001), being GFR the only determinant of the former by a stepwise regression. Dividing the study population according to an eGFR cut-off (80 and80 ml/min/1.73 m(2));80 women, in comparison with80, showed a significantly lower LVMI and lower size of aortic bulb, further reduced in the HRT+.In a cohort of healthy, drug-naïve, postmenopausal women, HRT seems to positively affect glomerular filtration and is associated with lower values of left ventricular mass and aortic root size, thus offering a further mechanism through female hormones exert cardioprotection