p66Shc regulates both steady-state and environmental stress-dependent reactive oxygen species (ROS) generation. Its deletion was shown to confer resistance to oxidative stress and protect mice from aging-associated vascular disease. This study was aimed at verifying the hypothesis that p66Shc deletion also protects from diabetic glomerulopathy by reducing oxidative stress. Streptozotocin-induced diabetic p66Shc knockout (KO) mice showed less marked changes in renal function and structure, as indicated by the significantly lower levels of proteinuria, albuminuria, glomerular sclerosis index, and glomerular and mesangial areas. Glomerular content of fibronectin and collagen IV was also lower in diabetic KO versus wild-type mice, whereas apoptosis was detected only in diabetic wild-type mice. Serum and renal tissue advanced glycation end products and plasma isoprostane 8-epi-prostaglandin F2␣ levels and activation of nuclear factor B (NF-B) were also lower in diabetic KO than in wild-type mice. Mesangial cells from KO mice grown under high-glucose conditions showed lower cell death rate, matrix production, ROS levels, and activation of NF-B than those from wild-type mice. These data support a role for oxidative stress in the pathogenesis of diabetic glomerulopathy and indicate that p66Shc is involved in the molecular mechanism(s) underlying diabetes-induced oxidative stress and oxidant-dependent renal injury.

We previously showed that mice lacking galectin-3/AGE-receptor 3 develop accelerated diabetic glomerulopathy. To further investigate the role of galectin-3/AGE-receptor function in the pathogenesis of diabetic renal disease, galectin-3 knockout (KO) and coeval wild-type (WT) mice were injected for 3 months with 30 microg/day of N(epsilon)-carboxymethyllysine (CML)-modified or unmodified mouse serum albumin (MSA). Despite receiving equal doses of CML, KO had higher circulating and renal AGE levels and showed more marked renal functional and structural changes than WT mice, with significantly higher proteinuria, albuminuria, glomerular, and mesangial area and glomerular sclerosis index. Renal 4-hydroxy-2-nonenal content and NFkappaB activation were also more pronounced in KO-CML vs. WT-CML. Kidney mRNA levels of fibronectin, laminin, collagen IV, and TGF-beta were up-regulated, whereas those of matrix metalloproteinase-2 and -14 were down-regulated, again more markedly in KO-CML than WT-CML mice. Basal and CML-induced RAGE and 80K-H mRNA levels were higher in KO vs. WT mice. MSA injection did not produce any significant effect in both genotypes. The association of galectin-3 ablation with enhanced susceptibility to AGE-induced renal disease, increased AGE levels and signaling, and altered AGE-receptor pattern indicates that galectin-3 is operating in vivo as an AGE receptor to afford protection toward AGE-dependent tissue injury.

Galectin-3 has been increasingly recognized as an important modulator of several biological functions, by interacting with several molecules inside and outside the cell, and an emerging player in numerous disease conditions. Galectin-3 exerts various and sometimes contrasting effects according to its location, type of injury or site of damage. Strong evidence indicates that galectin-3 participates in the pathogenesis of diabetic complications via its receptor function for advanced glycation end-products (AGEs) and advanced lipoxidation end-products (ALEs). AGEs/ALEs are produced to an increased extent in target organs of complications, such as kidney and vessels; here, lack of galectin-3 impairs their removal, leading to accelerated damage. In contrast, in the liver, AGE/ALE tissue content and injury are decreased, because lack of galectin-3 results in reduced uptake and tissue accumulation of these by-products. Some of these effects can be explained by changes in the expression of receptor for AGEs (RAGE), associated with galectin-3 deletion and consequent changes in AGE/ALE tissue levels. Furthermore, galectin-3 might exert AGE/ALE- and RAGE-independent effects, favoring resolution of inflammation and modulating fibrogenesis and ectopic osteogenesis. These effects are mediated by intracellular and extracellular galectin-3, the latter via interaction with N-glycans at the cell surface to form lattice structures. Recently, galectin-3 has been implicated in the development of metabolic disorders because it favors glucose homeostasis and prevents the deleterious activation of adaptive and innate immune response to obesogenic/diabetogenic stimuli. In conclusion, galectin-3 is an emerging all-out player in metabolic disorders and their complications that deserves further investigation as the potential target of therapeutic intervention.

17β-Oestradiol (E 2 )-mediated inhibition of angiotensin-converting enzyme (ACE) protects the E 2 -replete kidney from the progression of hypertensive renal disease. Angiotensin-converting enzyme 2 (ACE2), a homologue of ACE, counters the actions of ACE by catalysing the conversion of angiotensin II (Ang II) to angiotensin(1-7) [Ang(1-7)]. We investigated E 2 regulation of ACE2 in the renal wrap (RW) model of hypertension in rats. After 6 weeks on a high-sodium diet (4% NaCl), the activity of ACE2 was reduced in the renal cortex by 31%, which was mirrored by similar decreases in ACE2 protein (30%) and mRNA expression (36%) in the ovariectomized RW rat (RW-OVX); E 2 replacement prevented these effects. The RW-OVX rats exhibited greater renal injury, including 1.7-fold more tubulointerstitial fibrosis and 1.6-fold more glomerulosclerosis than E 2 -replete females (RW-Intact and RW-OVX+E 2 ). Angiotensin(1-7) infusion prevented these exacerbating effects of ovariectomy on renal pathology; no differences in indicators of renal injury were observed between RW-OVX-Ang(1-7) and RW-Intact rats. These renal protective effects of Ang(1-7) infusion were not attributable to increased ACE2 activity or to changes in heart rate or body weight, since these parameters were unchanged by Ang(1-7) infusion. Furthermore, Ang(1-7) infusion did not attenuate renal injury by reducing mean arterial pressure (MAP), since infusion of the peptide did not lower MAP but rather caused a slight increase during a 6 week chronic treatment for Ang(1-7). These results suggest that E 2 -mediated upregulation of renal ACE2 and the consequent increased Ang(1-7) production contribute to E 2 -mediated protection from hypertensive renal disease. These findings have implications for E 2 -deficient women with hypertensive renal disease and suggest that therapeutics targeted towards increasing ACE2 activity and Ang(1-7) levels will be renal protective.

These findings indicate that sexual dimorphism exists in remnant kidney growth and function two months following UNX. Indeed, morphological abnormalities and impairment in renal phosphate handling are affected by gonadal steroids by two-months post-UNX. The fact that renal Pi transport was reduced in female but not male UNX rats may also have important implications during periods of high metabolic demand for phosphate in the female.