Impact of Diabetes on Renal Transporters in Females and Males
PROJECT SUMMARY (See instructions): The diabetes complication addressed in this DiaComp pilot proposal is diabetic nephropathy (DN). 25% of people in US are obese and another 35% are overweight. 10% of the people in US have diabetes. 32% of people in US have hypertension. 1 in 10 Americans have chronic kidney disease. 500,000 people are on dialysis at a cost to Medicare exceeding $ 40 billion. These issues are closely interrelated as diabetes raises blood pressure and hypertension provokes insulin resistance. Additionally, the kidney contains the blood pressure set point as well as key therapeutic targets for diabetes (inhibitors of renin angiotensin system and SGLT2). Significant sex disparities are evident in the incidence and treatment outcomes of DN in humans as well as rodent models of DN. The broad long-term objective of this proposal is to define sexual dimorphisms in the renal tubular responses to type 2 diabetes (T2D) as a basis for optimizing sex specific therapies. We recently reported the sexual dimorphic profile of renal transporters and channels as well as the impact on electrolyte homeostasis in normal baseline Sprague Dawley rats and C57Bl/6J mice. Notably, females exhibited lower proximal transport (less NHE3 activation, less NaPi2), coupled to higher distal sodium reabsorption (more NCC, ENaC activation) facilitating more rapid excretion of a saline challenge as well as lowers plasma K+ set point. Our modelling of the female vs male proximal tubule revealed the necessity for higher Na+-glucose transporter (SGLT2) abundance in females vs. males to reabsorb the filtered load, reported experimentally. The ability to detect renal transporters sloughed into the tubule fluid and urine in exosomes provides a set of biomarkers for transporter activation along the nephron at baseline and during diabetes that can be verified in rodents and applied to humans. We propose to: Aim 1. Determine the impact of T2D in both males and females in two accepted and widely studied models of DN: 1) obese (vs. lean) ZSF1 rats, 2) db/db (vs db/m) C57BL/6J mice. Provide transporter profiles (abundance covalent modification and distribution) of renal Na+, K+, HCO3-, glucose, organic acid transporters, claudins, water and K+ channels and associated regulators. Assess physiologic and hemodynamic impact by measuring urine and plasma responses, blood pressure and GFR. Aim 2. Implement protocols to assess transporter activation by phosphorylation or cleavage in urine exosomes collected overnight in ZSF1 rats and in a set of urines on hand from Nephrology clinic (both M and F). Assess NHE3-P/ NHE3, NKCC-P/NKCC, NCC-P/NCC, and ENaCg full length/cleaved. RELEVANCE (See instructions): According to World Health Organization, Chronic Kidney Disease (CKD) is the 12th leading cause of death, 17th leading cause of disability in the world. More than 40% of CKD is due to type 2 diabetes (T2D). In the US, more than 500,000 people are on dialysis at a cost to Medicare exceeding $40 billion/yr. There are significant sex disparities in the epidemiology and outcomes of CKD. We aim to define renal tubular responses to T2D in females vs. male rodent models and in urinary biomarkers in both rodents and humans.

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