Over the past decade, we have developed a tubular hypothesis of glomerular filtration to account for several nuances of kidney function in early diabetes. The theory was first applied to diabetic hyperfiltration and we have demonstrated that the overriding stimulus comes from the proximal tubule where an early increase in reabsorption leads to a rise in single nephron GFR (SNGFR) through the normal physiologic actions of tubuloglomerular feedback (TGF). Another feature of the proximal tubule in early diabetes is that it assumes increased responsibility for salt balance. This salt sensitivity of the proximal tubule is responsible for the so-called "salt paradox" in early diabetes where changes in proximal reabsorption encounter an intact TGF system leading to a reciprocal effect of dietary salt on GFR. What confers heightened salt-sensitivity on the diabetic proximal tubule is unknown, although hypertrophy, per se, seems to be involved. The focus of this research will continue to be on events that befall the kidney early in diabetes, long before injury develops.
We aim to better understand the molecular mechanisms involved in proximal hyperreabsorption, glomerular hyperfiltration and kidney growth in the early diabetic kidney with the assumption that early diabetes-induced changes are important for the long-term outcome. During hyperglycemia, the kidney may sense hyperglycemia via tubular glucose uptake and a high fraction of overall proximal tubular reabsorption is linked, directly or indirectly, to sodium-glucose co-transport via SGLT1 andSGLT2. This prompted us to consider in, Specific Aim 1, the role of these SGLTs as controllers of proximal reabsorption, glomerular filtration, and kidney hypertrophy in early diabetes and as effectors of progression in a standard mouse model of diabetic nephropathy. The core methodology will continue to be renal clearance and micropuncture in the rat and mouse, including gene-targeted mice lacking SGLT1 and SGLT2,which we have in hand. A more novel effector of proximal reabsorption is the incretin, glucagon-like peptide 1(GLP-1), which has outstanding potential as a proximal diuretic. GLP-1 is degraded by the depeptidyl peptidase 4(DPP-4), which is co-expressed with the GLP-1 receptor in proximal tubular brush border. Both GLP-1 and DPP-4activity are altered in diabetes.
Specific Aim 2 is designed to understand the role of the GLP-1 / GLP-1 receptor system and DPP-4 as determinants of proximal reabsorption and glomerular filtration. Studies will employ clearance and micropuncture in the pharmacologically manipulated rats , genetically manipulated mice lacking the GLP-1 receptor, and wild type transplanted with GLP-1 receptor null kidneys. In addition we will use specific pharmacological tools to perturb this system, including DPP-4 inhibitors and GLP-1 agonists, which are currently used to augment insulin secretion in patients with type 2 diabetes.
Specific Aim 3 is to determine impacts of renal SGLT and incretin signaling beyond the kidney, namely on blood pressure and salt balance.

Public Health Relevance

Diabetes affects the kidney in stages. At the very onset of diabetes, the kidney grows large and GFR becomes supranormal. Recent basic and clinical research on the diabetic kidney is weighted toward sclerosis and kidney failure that occur many years later. The contemporary management of patients with diabetes is aimed toward slowing the progression to kidney failure after the onset of proteinuria and sclerosis. To prevent diabetic nephropathy altogether would be preferable, but to accomplish this we first need to understand earlier events that antedate renal injury. There is a longstanding idea that the early hemodynamic phenotype provokes the subsequent demise of a diabetic kidney. This research focuses on that early stage of diabetes, before there is injury or sclerosis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK056248-13
Application #
8325115
Study Section
Cellular and Molecular Biology of the Kidney Study Section (CMBK)
Program Officer
Rys-Sikora, Krystyna E
Project Start
1999-09-15
Project End
2015-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
13
Fiscal Year
2012
Total Cost
$362,937
Indirect Cost
$106,263
Name
Veterans Medical Research Fdn/San Diego
Department
Type
DUNS #
933863508
City
San Diego
State
CA
Country
United States
Zip Code
92161
Fu, Yiling; Gerasimova, Maria; Batz, Falk et al. (2015) PPAR? agonist-induced fluid retention depends on ?ENaC expression in connecting tubules. Nephron 129:68-74
Gailly, P; Szutkowska, M; Olinger, E et al. (2014) P2Y2 receptor activation inhibits the expression of the sodium-chloride cotransporter NCC in distal convoluted tubule cells. Pflugers Arch 466:2035-47
Vallon, Volker (2014) Do tubular changes in the diabetic kidney affect the susceptibility to acute kidney injury? Nephron Clin Pract 127:133-8
Borsting, Emily; Patel, Shalin V; Declèves, Anne-Emilie et al. (2014) Tribbles homolog 3 attenuates mammalian target of rapamycin complex-2 signaling and inflammation in the diabetic kidney. J Am Soc Nephrol 25:2067-78
Kumar, Rajiv; Vallon, Volker (2014) Reduced renal calcium excretion in the absence of sclerostin expression: evidence for a novel calcium-regulating bone kidney axis. J Am Soc Nephrol 25:2159-68
Blantz, Roland C; Singh, Prabhleen (2014) Glomerular and tubular function in the diabetic kidney. Adv Chronic Kidney Dis 21:297-303
Vallon, Volker; Docherty, Neil G (2014) Intestinal regulation of urinary sodium excretion and the pathophysiology of diabetic kidney disease: a focus on glucagon-like peptide 1 and dipeptidyl peptidase 4. Exp Physiol 99:1140-5
Vallon, Volker; Gerasimova, Maria; Rose, Michael A et al. (2014) SGLT2 inhibitor empagliflozin reduces renal growth and albuminuria in proportion to hyperglycemia and prevents glomerular hyperfiltration in diabetic Akita mice. Am J Physiol Renal Physiol 306:F194-204
Declèves, Anne-Emilie; Sharma, Kumar; Satriano, Joseph (2014) Beneficial Effects of AMP-Activated Protein Kinase Agonists in Kidney Ischemia-Reperfusion: Autophagy and Cellular Stress Markers. Nephron Exp Nephrol :
Rieg, Timo; Masuda, Takahiro; Gerasimova, Maria et al. (2014) Increase in SGLT1-mediated transport explains renal glucose reabsorption during genetic and pharmacological SGLT2 inhibition in euglycemia. Am J Physiol Renal Physiol 306:F188-93

Showing the most recent 10 out of 100 publications