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Impact of Diabetes on Renal Transporters in Females and Males
Summary Data Summary
Applicant McDonough, Alicia
E-Mail Address mcdonoug@usc.edu
Project Title Impact of Diabetes on Renal Transporters in Females and Males
CBU ID 18AU3932
External SubContract ID 32307-23
Diabetic Complication Nephropathy
Funding Program Group Pilot & Feasibility [PF2018]
Abstract PROJECT SUMMARY (See instructions): The diabetes complication addressed in this
¿´Æ¬ÊÓƵ 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.
Application PDF Application Research Plan
Status Contract Executed
Key Personnel McDonough, Alicia Ann
Salary Total Costs 40440
Supply Total Costs 20166
Equipment Total Costs 0
Travel/Other Total Costs 0
Direct Costs 60606
Indirect Costs Proposed 39394
Total Costs Proposed 100000
Total Costs Approved 100000
Start Date 11/1/2018
End Date 2/29/2020
IFO Name Lee, Cindy
IFO E-Mail Address cmlee@usc.edu
IACUC/IRB No. HS-13-00523
IACUC/IRB Institution Other
Entity ID No.
Report Request Date 2/29/2020
T1D NO
TypeCount
Invoices 26
Progress Reports 1
Data Submission


Invoices
UrlCBU IDExternal IDInstitutionDateDirectIndirectInvoiceBalancePDF
  View  18AU393232307-23Other9/9/2019$1,214.43$789.38$2,003.81$178.14View PDF
  View  18AU393232307-23Other9/14/2020$821.48$533.96$1,355.44$178.14View PDF
  View  18AU393232307-23Other8/11/2020$856.92$557.00$1,413.92$178.14View PDF
  View  18AU393232307-23Other7/28/2020$2,262.96$1,470.93$3,733.89$178.14View PDF
  View  18AU393232307-23Other7/27/2019$2,741.30$1,781.84$4,523.14$178.14View PDF
  View  18AU393232307-23Other6/6/2019$3,535.76$2,298.25$5,834.01$178.14View PDF
  View  18AU393232307-23Other6/5/2020$1,732.09$1,125.86$2,857.95$178.14View PDF
  View  18AU393232307-23Other6/5/2020$1,732.09$1,125.86$2,857.95$178.14View PDF
  View  18AU393232307-23Other5/3/2019$3,667.17$2,383.66$6,050.83$178.14View PDF
  View  18AU393232307-23Other5/19/2021$8,014.08$5,209.15$13,223.23$178.14View PDF
  View  18AU393232307-23Other5/12/2020$1,732.08$1,125.85$2,857.93$178.14View PDF
  View  18AU393232307-23Other4/9/2020$1,903.55$1,237.31$3,140.86$178.14View PDF
  View  18AU393232307-23Other4/7/2021$3,199.81$2,079.88$5,279.69$178.14View PDF
  View  18AU393232307-23Other4/2/2019$218.45$141.99$360.44$178.14View PDF
  View  18AU393232307-23Other3/5/2020$2,175.38$1,413.99$3,589.37$178.14View PDF
  View  18AU393232307-23Other3/3/2021$2,745.34$1,784.47$4,529.81$178.14View PDF
  View  18AU393232307-23Other2/5/2021$1,555.24$1,010.91$2,566.15$178.14View PDF
  View  18AU393232307-23Other2/5/2020$2,341.80$1,522.17$3,863.97$178.14View PDF
  View  18AU393232307-23Other12/7/2020$596.65$387.83$984.48$178.14View PDF
  View  18AU393232307-23Other12/6/2019$3,474.01$2,258.11$5,732.12$178.14View PDF
  View  18AU393232307-23Other11/6/2019$8,984.98$5,840.23$14,825.21$178.14View PDF
  View  18AU393232307-23Other11/5/2020$821.48$533.96$1,355.44$178.14View PDF
  View  18AU393232307-23Other10/8/2020$821.48$533.96$1,355.44$178.14View PDF
  View  18AU393232307-23Other10/7/2019$1,887.38$1,226.80$3,114.18$178.14View PDF
  View  18AU393232307-23Other1/8/2021$409.64$266.26$675.90$178.14View PDF
  View  18AU393232307-23Other1/8/2020-$1,736.70$1,736.70$178.14View PDF
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