Abstract
The kidney plays an essential role in homeostasis, accomplished through the regulation of pH, electrolytes and fluids, by the building blocks of the kidney, the nephrons. One of the important markers of the proper functioning of a kidney is the glomerular filtration rate. Diabetes is characterized by an enlargement of the glomerular and tubular size of the kidney, affecting the afferent and efferent arteriole resistance and hemodynamics, ultimately leading to chronic kidney disease. We postulate that the diabetes-induced changes in kidney may exhibit significant sex differences as the distribution of renal transporters along the nephron may be markedly different between women and men, as recently shown in rodents. The goals of this study are to (i) analyze how kidney function is altered in male and female patients with diabetes, and (ii) assess the renal effects, in women and men, of an anti-hyperglycemic therapy that inhibits the sodium-glucose cotransporter 2 (SGLT2) in the proximal convoluted tubules. To accomplish these goals, we have developed computational models of kidney function, separate for male and female patients with diabetes. The simulation results indicate that diabetes enhances Na+ transport, especially along the proximal tubules and thick ascending limbs, to similar extents in male and female patients, which can be explained by the diabetes-induced increase in glomerular filtration rate. Additionally, we conducted simulations to study the effects of diabetes and SGLT2 inhibition on solute and water transport along the nephrons. Model simulations also suggest that SGLT2 inhibition raises luminal [Cl–] at the macula densa, twice as much in males as in females, and could indicate activation of the tubuloglomerular feedback signal. By inducing osmotic diuresis in the proximal tubules, SGLT2 inhibition reduces paracellular transport, eventually leading to diuresis and natriuresis. Those effects on urinary excretion are blunted in women, in part due to their higher distal transport capacity.
Highlights
We simulate two diabetic conditions: (1) Moderate diabetes: plasma glucose is elevated from its non-diabetic value of 5–8.6 mM; single-nephron glomerular filtration rate (SNGFR) is increased by 27% (Mogensen, 1971); the tubular diameter and length of the proximal tubules are increased by 10%; and the diameter and length of the distal segments are increased by 18 and 7% (Baumgartl et al, 1998; Layton et al, 2016a); (2) Severe diabetes: plasma glucose is further increased to 20 mM; SNGFR is increased by 10% (Mogensen, 1971); the tubular diameter and length of the proximal tubules are increased by 28%; the diameter and length of the distal segments are increased by 42 and 7%, respectively (Baumgartl et al, 1998; Layton et al, 2016a)
We investigate the change in solute and water transport along the nephrons due to diabetes, and if those changes differ between men and women
Diabetes induces glomerular hyperfiltration and tubular hypertrophy, to different extents depending on the severity of the disease
Summary
The role of sex and gender has emerged as a priority area in biological and medical research (Layton, 2021). There has been increasing evidence that sex has a significant impact on the pathogenesis of metabolic disorders, such as type 2 diabetes (T2D). Diabetes prevalence is currently estimated to be 9.3% (463 million people) worldwide and expected to reach. T2D is associated with chronic kidney disease (Foley and Collins, 2007) and increases the risk of cardiovascular disease (Koye et al, 2018). Sex-specific differences have been reported in the disease prevalence and incidence of diabetes and diabetic kidney disease. Men are predisposed at a higher rate to T2D and a similar prevalence of type 1 diabetes (T1D) compared with premenopausal women. Postmenopausal women, have an increased risk of developing glomerular hyperfiltration, diabetic kidney disease, and end-stage kidney disease, compared to age-matched men (Bjornstad and Cherney, 2018; Lovshin et al, 2018)
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