Reno-protective effect of protocatechuic acid is independent of sex-related differences in murine model of UUO-induced kidney injury.

BACKGROUND: Obstructive nephropathy is a condition often caused by urinary tract obstruction either anatomical (e.g., tumors), mechanical (e.g., urolithiasis), or compression (e.g., pregnancy) and can progress to chronic kidney disease (CKD). Studies have shown sexual dimorphism in CKD, where males were found to have a more rapid decline in kidney function following kidney injury compared to age-matched females. Protocatechuic acid (PCA), an anti-oxidant and anti-inflammatory polyphenolic compound, has demonstrated promising effects in mitigating drug-induced kidney injuries. The current study aims to explore sexual dimorphism in kidney injury after unilateral ureteral obstruction (UUO) and assess whether PCA treatment can mitigate kidney injury in both sexes. METHODS: UUO was induced in 10-12 weeks old male and female C57BL/6J mice. Mice were categorized into four groups (n = 6-8/group); Sham, Sham plus PCA (100 mg/kg, I.P daily), UUO, and UUO plus PCA. RESULTS: After 2 weeks of induction of UUO, markers of kidney oxidative stress (TBARs), inflammation (IL-1α and IL-6), tubular injury (neutrophil gelatinase-associated lipocalin, NGAL and urinary kidney injury molecule-1, KIM-1), fibrosis (Masson's trichrome staining, collagen IV expression, MMP-2 and MMP-9) and apoptosis (TUNEL+ cells, active caspase-1 and caspase-3) were significantly elevated in both males and females relative to their sham counterparts. Males exhibited significantly greater kidney oxidative stress, inflammation, fibrosis, and apoptosis after induction of UUO when compared to females. PCA treatment significantly attenuated UUO-induced kidney injury, inflammation, fibrosis, and apoptosis in both sexes. CONCLUSION: Our findings suggest a differential gender response to UUO-induced kidney injury with males being more sensitive to UUO-induced kidney inflammation, fibrosis, and apoptosis than age-matched females. Importantly, PCA treatment reduced UUO-induced kidney injury in a sex-independent manner which might be attributed to its anti-oxidant, anti-inflammatory, anti-fibrotic, and anti-apoptotic properties.

Endogenous estradiol contributes to vascular endothelial dysfunction in premenopausal women with type 1 diabetes.

BACKGROUND: Endogenous estrogen is cardio-protective in healthy premenopausal women. Despite this favorable action of estrogen, animal models depict a detrimental effect of estradiol on vascular function in the presence of diabetes. The present study sought to determine the role of endogenous estradiol on endothelial function in women with type 1 diabetes. METHOD: 32 women with type 1 diabetes (HbA1c = 8.6 ± 1.7%) and 25 apparently healthy women (HbA1c = 5.2 ± 0.3%) participated. Flow-mediated dilation (FMD), a bioassay of nitric-oxide bioavailability and endothelial function was performed during menses (M) and the late follicular (LF) phase of the menstrual cycle to represent low and high concentrations of estrogen, respectively. In addition, a venous blood sample was collected at each visit to determine circulating concentrations of estradiol, thiobarbituric acid reactive substances (TBARS), and nitrate/nitrite (NOx), biomarkers of oxidative stress and nitric oxide, respectively. Data were collected in (1) 9 additional women with type 1 diabetes using oral hormonal birth control (HBC) (HbA1c = 8.3 ± 2.1%) during the placebo pill week and second active pill week, and (2) a subgroup of 9 demographically matched women with type 1 diabetes not using HBC (HbA1c = 8.9 ± 2.1%). RESULTS: Overall, estradiol was significantly increased during the LF phase compared to M in both type 1 diabetes (Δestradiol = 75 ± 86 pg/mL) and controls (Δestradiol = 71 ± 76 pg/mL); however, an increase in TBARS was only observed in patients with type 1 diabetes (ΔTBARS = 3 ± 13 µM) compared to controls (ΔTBARS = 0 ± 4 µM). FMD was similar (p = 0.406) between groups at M. In addition, FMD increased significantly from M to the LF phase in controls (p = 0.024), whereas a decrease was observed in type 1 diabetes. FMD was greater (p = 0.015) in patients using HBC compared to those not on HBC, independent of menstrual cycle phase. CONCLUSION: Endogenous estradiol increases oxidative stress and contributes to endothelial dysfunction in women with diabetes. Additionally, HBC use appears to be beneficial to endothelial function in type 1 diabetes.