Lipid Nephrotoxicity and Increased Risk of Nephrolithiasis in Model of Estrogen Deficiency

Abstract

Menopause is a period during which women tend to gain body fat. Estrogen deficiency is proposed to impact body fat composition and energy balance in these women by influencing the levels of leptin, an adipocyte‐derived hormone that acts primarily on the central nervous system. Specifically, lipid nephrotoxicity increases the risk for kidney disease and nephrolithiasis due to renal lipid accumulation and overly acidic urinary pH. Mechanisms underlying these kidney disturbances and extent of their effects when women become estrogen deficient (i.e. post‐menopausal) are not well‐defined. Utilizing an estrogen deficient (i.e. ovariectomized) rodent model, we hypothesize that central leptin receptor activation regulates renal function by augmenting the accumulation of renal lipids and urinary pH acidification. We measured the glomerular filtration rate (GFR) by creatinine clearance and protein level of the neutrophil gelatinase‐associated lipocalin (NGAL), an early biomarker of kidney injury, by immunohistochemistry. An increase in creatinine clearance (from 1.3 ml/min to 2.3 ml/min) and protein levels of NGAL (over 90% increase in both glomeruli and tubules) was measured in ovariectomized adult female rats when compared with their sham‐operated controls. Treatment with leptin receptor antagonist (LAN‐6, 3μg/day), delivered for four weeks into the lateral ventricle by an osmotic pump, significantly attenuated these effects. Furthermore, we determined that perirenal fat accumulation was markedly higher in the same estrogen deficiency model when compared with the sham‐operated control. Perirenal fat accumulation has been associated with lipid accumulation in renal tissues and excess of intrarenal lipid is increasingly recognized to contribute to kidney injury through lipotoxicity. A significant accumulation of renal lipid, tested using oil red O staining, was detected in the renal tubules of the ovariectomized animals when compared with their controls. We also found significant acidification of urinary pH and decreased protein expression of a key player in urinary pH regulation, Na/H exchanger‐3 (NHE3), in ovariectomized animals when compared with their controls. Renal lipid accumulation, urinary pH acidification and decrease in NHE3 expression were all partially reversed by blocking activation of central leptin receptors. We propose that: 1. An increase in GFR combined with kidney injury presupposes kidney dysfunction, 2. infiltration of renal lipid leads to renal injury, through lipotoxicity, 3. urinary pH acidification and reduction of NHE3 expression increases the risk of nephrolithiasis. Taken together, these findings suggest that leptin plays a key role in the development of menopausal‐associated kidney disease.