Diabetes mellitus is the leading cause of end-stage renal disease in the United States. Early diabetes is characterized by glomerular hyperfiltration and increased kidney size. Furthermore, diabetes alters the renal vascular response to a variety of physiologic stimuli including changes in perfusion pressure, salt intake, and protein feeding. While intrarenal hemodynamic abnormalities are potentially critical to the pathogenesis of diabetic nephropathy, the elemental cause of these abnormalities is poorly understood. It is the general purpose of the proposed research to examine the basis for the cardinal renal hemodynamic abnormalities in the rat with streptozotocin diabetes. This model will be studied by a variety of micropuncture and in vitro techniques. Attention will focus on interactions between the glomerulus and proximal tubule and on the mediators responsible for paradoxical reactions of the diabetic kidney to changes in dietary salt and other stimuli. Along the way, studies will address three specific aims.
The first aim i s to discover whether diabetic glomerular hyperfiltration is a consequence of altered tubuloglomerular feedback (TGF). This will be achieved by determining whether or not the onset of hyperfiltration requires a prior increase in proximal reabsorption which deactivates TGF, by assessing the contribution of decreased TGF efficiency to hyperfiltration, and by examining whether diabetes alters the way in which TGF adapts to changes in tubular function.
The second aim i s to explain the paradoxical tendency for dietary salt restriction to exacerbate diabetic hyperfiltration and hypertrophy. The basic abnormality is presumed to involve an imbalance between competing vasoconstrictors and vasodilators, each activated during salt restriction. Attention will focus on the ability to modulate the renin-angiotensin and nitric oxide systems and on interactions between dietary salt and diabetes in the control of proximal tubular growth and function.
The third aim i s to understand the mechanism(s) which underlie the renal hemodynamic effects of angiotensin converting enzyme inhibitors (ACEI) in diabetes. Studies will focus on the roles of bradykinin, the heptapeptide ANG (1-7), and alternative ANG II second messenger systems (NADH/NADPH oxidase, and hemoxygenase). Understanding why ACEI renders the diabetic kidney capable of modulating its internal hemodynamics will provide insight into the mechanisms which underlie the salutary effect of ACEI in diabetic patients and into the pathophysiology of the diabetic state.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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General Medicine B Study Section (GMB)
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Rys-Sikora, Krystyna E
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Veterans Medical Research Fdn/San Diego
San Diego
United States
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Thomson, Scott C; Vallon, Volker (2018) Renal Effects of Incretin-Based Diabetes Therapies: Pre-clinical Predictions and Clinical Trial Outcomes. Curr Diab Rep 18:28
Hallow, K Melissa; Gebremichael, Yeshitila; Helmlinger, Gabriel et al. (2017) Primary proximal tubule hyperreabsorption and impaired tubular transport counterregulation determine glomerular hyperfiltration in diabetes: a modeling analysis. Am J Physiol Renal Physiol 312:F819-F835
Vallon, Volker; Thomson, Scott C (2017) Targeting renal glucose reabsorption to treat hyperglycaemia: the pleiotropic effects of SGLT2 inhibition. Diabetologia 60:215-225
Gallo, Linda A; Ward, Micheal S; Fotheringham, Amelia K et al. (2016) Once daily administration of the SGLT2 inhibitor, empagliflozin, attenuates markers of renal fibrosis without improving albuminuria in diabetic db/db mice. Sci Rep 6:26428
Layton, Anita T; Vallon, Volker; Edwards, Aurélie (2016) Predicted consequences of diabetes and SGLT inhibition on transport and oxygen consumption along a rat nephron. Am J Physiol Renal Physiol 310:F1269-83
Layton, Anita T; Vallon, Volker; Edwards, Aurélie (2016) A computational model for simulating solute transport and oxygen consumption along the nephrons. Am J Physiol Renal Physiol 311:F1378-F1390
Layton, Anita T; Laghmani, Kamel; Vallon, Volker et al. (2016) Solute transport and oxygen consumption along the nephrons: effects of Na+ transport inhibitors. Am J Physiol Renal Physiol 311:F1217-F1229
Song, Panai; Onishi, Akira; Koepsell, Hermann et al. (2016) Sodium glucose cotransporter SGLT1 as a therapeutic target in diabetes mellitus. Expert Opin Ther Targets 20:1109-25
Vallon, Volker (2016) Tubular Transport in Acute Kidney Injury: Relevance for Diagnosis, Prognosis and Intervention. Nephron 134:160-166
Novikov, Aleksandra; Vallon, Volker (2016) Sodium glucose cotransporter 2 inhibition in the diabetic kidney: an update. Curr Opin Nephrol Hypertens 25:50-8

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