Sex differences in renal transporters: assessment and functional consequences

McDonough, Alicia A.; Harris, Autumn N.; Xiong, Lingyun; Layton, Anita T.

doi:10.1038/s41581-023-00757-2

Cited by 16 publications

(5 citation statements)

References 152 publications

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“…In C57BL/6 mice, SGLT2 protein expression is lower in females compared to males; however, Sglt2 mRNA expression showed the opposite 18 . In contrast, in Wistar rats, SGLT2 protein expression was higher in females compared to males 18 , 19 and Sglt2 mRNA expression in the renal cortex was similar 18 . In human kidneys no differences in SGLT2 expression were reported 20 .…”

Section: Discussionmentioning

confidence: 64%

Effect of SGLT2 inhibition on salt-induced hypertension in female Dahl SS rats

Kravtsova,

Levchenko,

Klemens

et al. 2023

Sci Rep

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Sodium-glucose co-transporters (SGLTs) in the kidneys play a pivotal role in glucose reabsorption. Several clinical and population-based studies revealed the beneficial effects of SGLT2 inhibition on hypertension. Recent work from our lab provided significant new insight into the role of SGLT2 inhibition in a non-diabetic model of salt-sensitive hypertension, Dahl salt-sensitive (SS) rats. Dapagliflozin (Dapa) blunted the development of salt-induced hypertension by causing glucosuria and natriuresis without changes in the Renin–Angiotensin–Aldosterone System. However, our initial study used male SS rats only, and the effect of SGLT2 inhibitors on hypertension in females has not been studied. Therefore, the goal of this study was to determine whether SGLT2 inhibition alters blood pressure and kidney function in female Dahl SS rats. The result showed that administration of Dapa for 3 weeks prevented the progression of salt-induced hypertension in female rats, similar to its effects in male SS rats. Diuresis and glucose excretion were significantly increased in Dapa-treated rats. SGLT2 inhibition also significantly attenuated kidney but not heart fibrosis. Despite significant effects on blood pressure, Dapa treatment caused minor changes to electrolyte balance and no effects on kidney and heart weights were observed. Our data suggest that SGLT2 inhibition in a non-diabetic model of salt-sensitive hypertension blunts the development of salt-induced hypertension independent of sex.

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Section: Discussionmentioning

confidence: 64%

Effect of SGLT2 inhibition on salt-induced hypertension in female Dahl SS rats

Kravtsova,

Levchenko,

Klemens

et al. 2023

Sci Rep

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“… 44 - 46 Additionally, PT energy expenditure in female rodents is thought to be lower than in males due to a greater reliance on the distal convoluted tubule for sodium reabsorption. 47 , 48 Together, these factors may contribute to the enhanced protection of female Lrp2 KO mice against WD-induced kidney injury. Understanding the relationship between diet and Lrp2 -mediated sex-dependent protection or injury may provide novel targets for managing obesity and T2D.…”

Section: Discussionmentioning

confidence: 99%

Megalin Knockout Reduces SGLT2 Expression and Sensitizes to Western Diet-induced Kidney Injury

Youm,

Shipman,

Albalawy

et al. 2024

Function

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Megalin (Lrp2) is a multiligand receptor that drives endocytic flux in the kidney proximal tubule (PT) and is necessary for the recovery of albumin and other filtered proteins that escape the glomerular filtration barrier. Studies in our lab have shown that knock out (KO) of Lrp2 in opossum PT cells leads to a dramatic reduction in sodium glucose co-transporter 2 (SGLT2) transcript and protein levels, as well as differential expression of genes involved in mitochondrial and metabolic function. SGLT2 transcript levels are reduced more modestly in Lrp2 KO mice. Here, we investigated the effects of Lrp2 KO on kidney function and health in mice fed regular chow (RC) or a Western-style diet (WD) high in fat and refined sugar. Despite a modest reduction in SGLT2 expression, Lrp2 KO mice on either diet showed increased glucose tolerance compared to control mice. Moreover, Lrp2 KO mice were protected against WD-induced fat gain. Surprisingly, renal function in male Lrp2 KO mice on WD was compromised, and the mice exhibited significant kidney injury compared with control mice on WD. Female Lrp2 KO mice were less susceptible to WD-induced kidney injury than male Lrp2 KO. Together, our findings reveal both positive and negative contributions of megalin expression to metabolic health, and highlight a megalin-mediated sex-dependent response to injury following WD.

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“…The sex difference in ammonia handling by the kidney is an ongoing research topic, which has been studied mainly in mice, so far [ 22 , 81 , 124 ]. A striking sex difference in mouse kidney lies in the structure of the kidney itself, seen both under baseline condition and during acid loading.…”

Section: Sex Differences In Ammonia Handling By the Kidneymentioning

confidence: 99%

State of knowledge on ammonia handling by the kidney

Bourgeois,

Houillier

2024

Pflugers Arch - Eur J Physiol

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The disposal of ammonia, the main proton buffer in the urine, is important for acid–base homeostasis. Renal ammonia excretion is the predominant contributor to renal net acid excretion, both under basal condition and in response to acidosis. New insights into the mechanisms of renal ammonia production and transport have been gained in the past decades. Ammonia is the only urinary solute known to be produced in the kidney and selectively transported through the different parts of the nephron. Both molecular forms of total ammonia, NH3 and NH4+, are transported by specific proteins. Proximal tubular ammoniagenesis and the activity of these transport processes determine the eventual fate of total ammonia produced and excreted by the kidney. In this review, we summarized the state of the art of ammonia handling by the kidney and highlighted the newest processes described in the last decade.

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Sex differences in renal transporters: assessment and functional consequences

Cited by 16 publications

References 152 publications

Effect of SGLT2 inhibition on salt-induced hypertension in female Dahl SS rats

Effect of SGLT2 inhibition on salt-induced hypertension in female Dahl SS rats

Megalin Knockout Reduces SGLT2 Expression and Sensitizes to Western Diet-induced Kidney Injury

State of knowledge on ammonia handling by the kidney

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