Gender Differences in the Progression of Experimental Chronic Kidney Disease Induced by Chronic Nitric Oxide Inhibition

Abstract

Chronic kidney disease (CKD) is considered a public health problem, assuming epidemic proportions worldwide. In this context, the preponderance of CKD prevalence in male over age-matched female patients is of note. In the present study, we investigated the impact of the gender on the development of experimental CKD induced by chronic nitric oxide (NO) inhibition in Wistar male and female rats through the administration of L-NAME. CKD model induced by L-NAME is characterized by systemic vasoconstriction, resulting in severe hypertension, albuminuria, renal ischemia, glomerulosclerosis, interstitial expansion, and macrophage infiltration. After 30 days of CKD induction, male NAME rats exhibited remarkable albuminuria, augmented cortical histological damage, interstitial inflammation, and fibrosis. Age-matched female NAME rats showed significantly lower albuminuria, diminished glomerular ischemia, and glomerulosclerosis, as well as a significant reduction in the expression of α-smooth muscle actin renal interstitial Ang II+ cells. Thus, the present study demonstrated that female rats submitted to the NAME model developed less severe CKD than males. Female renoprotection could be promoted by both the estrogen anti-inflammatory activity and/or by the lack of testosterone, related to renin-angiotensin-aldosterone system hyperactivation and fibrogenesis. However, the influence of sex hormones on the progression of CKD needs to be further investigated.

Understanding the opposite effects of sex hormones in mediating renal injury

“…The administration of 17‐beta oestradiol to hypertensive ovariectomized rats attenuates glomerulosclerosis and tubulointerstitial fibrosis 68 . Chronic inhibition of NO induced marked albuminuria, histological damage, interstitial inflammation and fibrosis in Wistar male rats, while females showed less severe damage 69 . In the renal damage induced by adenine, the renal function of females was decreased to a lesser extent than that of males, whereas the changes associated with CKD, such as oxidative stress, inflammation and renal fibrosis, were more pronounced in the males compared with the females 70 .…”

“…In addition, eNOS and NO levels decrease with aging in women, effects that are associated with the onset of menopause 81 . In Wistar rats with CKD caused by chronic inhibition of NOS, males exhibit a greater number of interstitial renal cells containing Ang II than females 69 . Additionally, oestrogens protect against the development of hypertension in rats by shifting the vasoconstrictor/vasodilator balance of the RAAS components as they increase the levels of Ang I to VII and reduce Ang II levels 82 .…”

“…In contrast, male rats developed proteinuria, and castration prevented this change, maintaining similar values as female rats. The oestrogen anti‐inflammatory activity and the lack of testosterone (related to renin‐angiotensin‐aldosterone system hyperactivation and fibrogenesis) were suggested as possible renoprotective mechanisms 69,85 . In addition, the loss of oestrogen contributes to the development of kidney disease associated with aging by down‐regulating eNOS and increasing renal inflammation, while oestrogen administration attenuates these alterations 86 .…”

“…Accordingly, the decrease in renal function was lower in females with adenine‐induced CKD than in male rats 70 . Males also developed more severe L‐NG‐Nitroarginine Methyl Ester (L‐NAME)‐induced CKD than females, which is characterized by remarkable albuminuria, histological damage, increased interstitial inflammation and fibrosis 69 . In male rats subjected to 5/6 nephrectomy, kidney damage was associated with an increase in interleukin (IL)‐6 and IL‐1beta levels, which was absent in females.…”

Serum lipid profile and Nephropathy in type 2 diabetes patients: A comparative study

“…A higher incidence and prevalence of renal failure particularly in non diabetic renal patients is observed in men. According to Silbiger and Neugarten, the ratio between men and women that reaches renal insufficiency due to hypertensive nephropathy or glomerulonephritis is 1.6 men for each woman affected [20] . Figure-1 there is a statistically significant large effect in FBS, PPBS, HbA1c, TAG, VLDL, HDL, and lipoprotein (a) levels of cases compared with controls, whereas LDL and cholesterol levels are no significant.…”