Recent advances in sex differences in kidney function

Besides the excretion of metabolic wastes, the kidneys regulate the balance of electrolytes, acid-base, and blood pressure (12, 23). Sex differences in renal function and blood pressure have been widely described across many species. With the newest hypertension guidelines defining hypertension as a systolic blood pressure greater than 130 mmHg and a diastolic blood pressure above 80 mmHg, almost half of the adult population in the United States is now classified as hypertensive; more women have hypertension than men (24), as do blacks compared with whites (14). As such, there remains a high degree of interest in gaining a better understanding of the mechanisms controlling blood pressure in both sexes. To that end, the American Journal of Physiology-Renal Physiology launched a recent Call for Papers on Sex and Gender in Renal Health and Function.

It is well established that young males have a higher blood pressure and a higher prevalence of hypertension compared with age-matched females in many mammalian and avian species (27). In humans (37) and in genetic models of hypertension such as spontaneously hypertensive rats (SHR) and Dahl salt-sensitive rats (20), males develop an earlier and more severe hypertension than females. To date, the mechanisms underlying male-female differences in blood pressure control remain poorly understood. In the past few years, an explosion of data has emerged concerning sex differences in nitric oxide (NO) (1), the renin-angiotensin aldosterone system (RAAS) (10, 13), inflammation (22, 31, 32), and in kidney function (19, 25). This editorial focus will highlight recent advances in our understanding of sex differences in kidney and related function, obtained from experimental and theoretical studies. Some of these studies were published in response to a recent Call for Papers of this journal, Sex and Gender in Renal Health and Function.

SEX DIFFERENCES IN RENAL FUNCTION

Exciting findings reported by Veiras et al. (36) have highlighted the fact that the kidney of a female rat is not simply a smaller version of a male kidney. Rather, male and female kidneys exhibit dimorphic patterns of transporter expression and salt handling (36), the implications of which could be profound in terms of renal function. Li et al. incorporated those findings into a computational model of solute and water transport along the proximal convoluted tubule of the rat kidney (16) and applied the resulting sex-specific models to investigate the functional implication of the sexual dimorphism in transporter patterns along that segment (18). The models account for the sex differences in expression levels of the apical and basolateral transporters, in single-nephron glomerular filtration rate, and in tubular dimensions. Model simulations indicate that the lower fractional volume reabsorption in the female can be attributed to their smaller transport area and lower aquaporin-1 expression level. Additionally, model results suggest that the higher sodium glucose cotransporter 2 (SGLT2) expression in the female (26) may compensate for its lower transport area to achieve a similar hyperglycemic tolerance as male. There remain few studies in the literature that have thoroughly investigated the basic physiological differences in renal structure and function, yet these studies underscore the importance of improving our understanding of the basic physiological characteristics of the female kidney.

Indeed, Harris et al. (9) studied sex differences in renal ammonia metabolism in the mouse kidney. Their findings indicate that the observed sex difference in basal ammonia metabolism can be attributed to fundamental sex differences in renal structure and in the expression of proteins involved in ammonia metabolism. More specifically, proximal tubules account for a larger percentage of the renal cortical parenchyma in the male kidney compared with females, whereas collecting ducts account for a lower percentage of the renal parenchyma than females. Furthermore, the expression of phosphoenolpyruvate carboxykinase (PEPCK), glutamine synthetase, Na⁺-K⁺-Cl⁻ cotransporter (NKCC2), Rhbg, and Rhcg was found to be higher in female mice, which may explain their higher basal ammonia excretion rate.

In a recent study by Crislip et al. (2), a role for renal medullary pericytes in ischemia-reperfusion (IR) injury was examined following IR injury in male and female SHR. Interestingly, vascular congestion exhibited a strong negative correlation with pericyte density in both sexes. Pericyte density was also negatively correlated with plasma creatinine, blood urea nitrogen (BUN), and tubular cast formation in female, but not male SHR. In contrast, tubular damage and pericyte density were negatively correlated with pericyte density only in males. These studies linked pericytes with recovery of function and protection against IR-induced injury in both sexes, although the mechanism by which pericytes offered this protection was sex-specific. Moreover, males tended to have a greater number of pericytes compared with females, and males exhibited a greater loss of pericytes following IR compared with females.

SEX DIFFERENCES IN MECHANISMS CONTROLLING RENAL FUNCTION AND BLOOD PRESSURE

NO is central to the control of vascular homeostasis and blood pressure and there are well-known sex differences in NO where females have greater NO bioavailability compared with males. To investigate sex differences in NO bioavailability, and their implications in the development of hypertension, Chen et al. (1) developed and applied the first sex-specific model for the renal medulla. Specifically, they applied computational models of oxygenation and transport of solutes in the kidneys of male and female spontaneously hypertensive rats (SHR) (3–5) to investigate the observed sex differences in NO levels. The male and female SHR models were assumed to differ in blood flow, single-nephron glomerular filtration rate (SNGFR), size, tubular transport, and metabolism. Model simulations indicate that, given the same transport and metabolic parameters, male and female rats have similar medullary O₂ and NO bioavailability. This result suggests that sex differences in kidney size and blood flow alone cannot account for the greater NO levels observed in female SHR compared with males (30). Instead, the greater NO bioavailability in female SHR may be the result of greater NO production or that of lower levels of NO scavenging by O₂⁻. Model simulation results suggest that medullary NO and Po₂ levels are highly sensitive to endothelial NO generate rates. Significantly higher medullary NO and Po₂ levels can be obtained even when the higher NO generation rates are limited to specific vascular segments. In contrast, NO and Po₂ levels were not sensitive to the potentially lower O₂⁻ production rate in female (and thus lower medullary O₂⁻ levels and lower levels of NO scavenging by O₂⁻).

As previously noted, there are numerous sex differences in the expression and activity of many components of the RAAS that have been well documented elsewhere (10, 13), where males have greater expression levels of the classical components of the RAAS and greater increases in blood pressure in response to angiotensin II compared with females. Indeed, sex differences in the RAAS are likely central in mediating sex differences in blood pressure control. Type 1A angiotensin receptors in vascular smooth muscle cells have been demonstrated to play a critical role in blood pressure regulation and hypertension in the male mice (7). Wolf et al. (38) examined the vascular effects of the RAAS in female mice for the first time. They found that elimination of type 1A angiotensin receptors in vascular smooth muscle cells in female mice reduced baseline blood pressure without altering sodium sensitivity. Female SMKO mice exhibit elevated urinary norepinephrine levels relative to control. There was a nearly complete elimination of angiotensin II-induced kidney hemodynamic responses with attenuation of acute vasoconstrictor responses in the systemic vasculature. These findings suggest that direct vascular actions of type 1A angiotensin receptors also play a key role in blood pressure control and hypertension pathogenesis of both sexes, although males and females were not directly compared in the same study making it difficult to assess any potential sex differences in overall outcomes. In another study examining the role of the RAAS and blood pressure control in men and women by Toering et al. (33) investigated aldosterone and extracellular volume in men and women on different sodium intakes. Men had greater extracellular volume and a higher blood pressure than women regardless of sodium intake and the authors suggest that sex differences in the regulation of aldosterone contribute to these fundamental physiological differences between men and women.

There continues to be significant interest in the role of immune cell activation in mediating injury and blood pressure in both sexes, and there is evidence to suggest that immune cells underlie sex differences in blood pressure. The well-established sex difference in the blood pressure response to angiotensin II in mice is abolished in Rag1^−/− mice that lack B and T cells (12, 22). Moreover, adoptive transfer of T cells from wild-type male mice reestablishes the enhanced blood pressure response in the male, whereas adoptive transfer from a female wild-type mouse into a male Rag1^−/− mouse does not, suggesting that T cells mediate the sex difference in angiotensin II hypertension. This literature was recently reviewed in Ref. 29, and it is postulated that greater expression of anti-inflammatory, antihypertensive T regulatory cells (Tregs) in females versus males is critical in attenuating increases in blood pressure and injury in the female relative to the male. To gain insight into the mechanism driving greater Treg expression in female kidneys, Tipton et al. (32) assessed the impact of neutralizing transforming growth factor (TGF)-β on blood pressure and Tregs in female SHR. TGF-β is critical for the differentiation of naïve T cells into the Treg phenotype, and females have greater renal TGF-β expression than males. Additional studies treated female SHR with TGF-β neutralizing antibody and reported no effect on blood pressure although a decrease in circulating Tregs with no significant change in renal Tregs was observed. While these studies did not explain the sex difference in renal T cells, the ability of a sex difference in cytokines to impact the immune cell profile should not be taken lightly. There are numerous reports of sex differences in cytokine levels in both humans and animal models of disease that could result in profound differences in immune cell activation and overall disease outcomes.

SEX DIFFERENCES IN DIABETES

Sex differences in disease are not limited to cardiovascular disease. Of interest, there are also sex differences in diabetes. While there is no consensus on whether sex plays a role in the prevalence of type 1 diabetes (T1D), women of European descent aged 15 to 40 years old are less likely to develop T1D than age-matched men (6). Also of interest is that the cardiovascular protection often observed in younger women is lost in diabetes (21).

In a study with human participants, Škrtić et al. (28) revealed significant sex-based differences in renal arteriolar resistance among T1D patients. Their findings indicate that among T1D patients with glomerular hyperfiltration, women exhibit higher efferent arteriolar resistance and filtration fraction and lower effective renal plasma flow, relative to the male patients; in contrast, no sex differences were observed in afferent arteriolar resistance. An implication of this result is that hyperfiltration in early T1D may disproportionally affect women and, in part, explain the loss of protection against the progression of kidney diseases in diabetic women.

Although conflicting evidence exists regarding any sex difference in the development and progression of diabetic nephropathy, estrogen is known to impact cellular processes involved in the pathophysiology of diabetic nephropathy. Given that the full-length estrogen receptor-α (ERα66) and its ERα splice variants are expressed in the kidney, Irsik and coworkers (11) conducted a study using streptozotocin (STZ)-induced diabetic female mice to assess the extent to which these splice variants inhibit the glomerular enlargement found in early T1D. They found evidence suggesting that the full-length ERα66 may protect female mice from T1D-induced glomerular hyperfiltration and proteinuria. Additionally, ERα splice variants were found to reduce glomerular area and cortical interstitial macrophage infiltration, although these effects were masked by ERα66 (11). Further studies which delineate estrogen signaling in the kidney and how they interact, may lead to therapeutic treatments that target the renoprotective estrogen receptors while minimizing negative side effects.

In recent years, SGLT2 inhibitors have emerged as a new and promising therapeutic approach for lowering blood glucose levels. In addition to its benefits in glycemic control, SGLT2 inhibitors have also been shown in animal studies to attenuate hyperfiltration (34, 35), and the underlying mechanisms have been investigated in computational modeling studies (8, 15, 17). Despite the interest in this new class of therapeutics, there is a surprising lack of studies in females. Sex-specific cardiovascular and renal benefits of SGLT2 inhibitors remain to be characterized.

CONCLUSIONS

It has become increasingly clear that experimental and clinical results obtained in one sex cannot be extrapolated to both sexes without sufficient justification. A better understanding of the sex differences in renal physiology and pathophysiology is a necessary step toward a true understanding of the complicated transport and excretion processes in the kidney, and, if needed, toward sex-specific and more effective therapeutic treatments for men and women.

GRANTS

This research was supported by the Canada 150 Research Chair program (A. T. Layton), the National Institutes of Health (National Institute of Diabetes and Digestive and Kidney Diseases Grant R01DK106102 to A. T. Layton and National Heart, Lung, and Blood Institute Grants R01NHLBI00180 and 5P01HL134604-03 to J. C. Sullivan), and American Heart Association Grant 17EIA33410565 (J. C. Sullivan).

DISCLOSURES

No conflicts of interest, financial or otherwise, are declared by the authors.

AUTHOR CONTRIBUTIONS

A.T.L. and J.C.S. drafted manuscript; A.T.L. and J.C.S. edited and revised manuscript; A.T.L. and J.C.S. approved final version of manuscript.