Sex-Specific Computational Models of Kidney Function in Patients With Diabetes
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 b...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2022-01-01
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| Series: | Frontiers in Physiology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fphys.2022.741121/full |
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| author | Sangita Swapnasrita Aurélie Carlier Anita T. Layton Anita T. Layton |
| author_facet | Sangita Swapnasrita Aurélie Carlier Anita T. Layton Anita T. Layton |
| author_sort | Sangita Swapnasrita |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-11T18:11:26Z |
| format | Article |
| id | doaj.art-f23d75ab958540679f57d7a9837fbc9f |
| institution | Directory Open Access Journal |
| issn | 1664-042X |
| language | English |
| last_indexed | 2024-04-11T18:11:26Z |
| publishDate | 2022-01-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Physiology |
| spelling | doaj.art-f23d75ab958540679f57d7a9837fbc9f2022-12-22T04:10:06ZengFrontiers Media S.A.Frontiers in Physiology1664-042X2022-01-011310.3389/fphys.2022.741121741121Sex-Specific Computational Models of Kidney Function in Patients With DiabetesSangita Swapnasrita0Aurélie Carlier1Anita T. Layton2Anita T. Layton3Department of Cell Biology-Inspired Tissue Engineering, MERLN Institute for Technology-Inspired Regenerative Medicine, Maastricht University, Maastricht, NetherlandsDepartment of Cell Biology-Inspired Tissue Engineering, MERLN Institute for Technology-Inspired Regenerative Medicine, Maastricht University, Maastricht, NetherlandsDepartment of Applied Mathematics, University of Waterloo, Waterloo, ON, CanadaDepartment of Biology, Cheriton School of Computer Science, School of Pharmacology, University of Waterloo, Waterloo, ON, CanadaThe 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.https://www.frontiersin.org/articles/10.3389/fphys.2022.741121/fullsex differencesdiabetes mellitusSGLT2 inhibitorsdiuresisnatriuresiskaliuresis |
| spellingShingle | Sangita Swapnasrita Aurélie Carlier Anita T. Layton Anita T. Layton Sex-Specific Computational Models of Kidney Function in Patients With Diabetes Frontiers in Physiology sex differences diabetes mellitus SGLT2 inhibitors diuresis natriuresis kaliuresis |
| title | Sex-Specific Computational Models of Kidney Function in Patients With Diabetes |
| title_full | Sex-Specific Computational Models of Kidney Function in Patients With Diabetes |
| title_fullStr | Sex-Specific Computational Models of Kidney Function in Patients With Diabetes |
| title_full_unstemmed | Sex-Specific Computational Models of Kidney Function in Patients With Diabetes |
| title_short | Sex-Specific Computational Models of Kidney Function in Patients With Diabetes |
| title_sort | sex specific computational models of kidney function in patients with diabetes |
| topic | sex differences diabetes mellitus SGLT2 inhibitors diuresis natriuresis kaliuresis |
| url | https://www.frontiersin.org/articles/10.3389/fphys.2022.741121/full |
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