This is a 5-year proposal for the development of the candidate as a physician scientist in the arena of renal physiology and pathophysiology. It will allow an extended period of research training in basic physiologic methods to accomplish this goal. The mentor, Dr. Blantz, is a well-recognized leader in the field of renal physiology and has mentored numerous trainees to achieve successful academic careers. UCSD provides an ideal fostering environment for young investigators with opportunities to interact and collaborate with many well-established investigators within and outside the Division of Nephrology. In chronic kidney disease (CKD), adaptations in remaining nephrons help maintain the primary functions of the kidney i.e. filtration and salt balance in the earlier stages. In the face of successive nephron loss, the kidney has pre-defined and limited sets of physical factors (glomerular and tubular) that can be altered to maintain GFR. In addition a change in the pre-existing environment can influence the response to subsequent injury. A relative resistance to decline in GFR has been observed by us after an ischemic event in early subtotal nephrectomy (STN) in rat, a model of CKD. Our investigations of the physiologic, metabolic and molecular milieu in early STN provide valuable insights into the overall response of the kidney to injury. At baseline, adaptations in nephron function include an absence of tubuloglomerular feedback (TGF) response, which can curtail the decline in GFR seen normally. Other glomerular and tubular factors, yet unexamined, could also be important. Finally in vivo preconditioing can afford resistance to proximal tubuar cells. Using micropuncture and molecular biology techniques we propose to provide useful mechanistic information.
The specific aims i nclude: 1) Determine the degree to which the relative insensitivity of GFR to IR in the early stage is due to differences in TGF, physical factors, and other humoral factors using a simple, yet inclusive, network construct applied to micropuncture data. 2) Determine the underlying mechanisms of cellular resistance to ischemia in STN and the role of hypoxia inducible factor and its downstream effects in this response. These will be the first detailed analysis of the mechanisms of acute kidney injury in the presence of CKD.

Public Health Relevance

Chronic kidney disease is a major health problem and acute kidney injury on pre-existing CKD is increasingly being recognized. There are important differences in AKI when it occurs on a background of CKD and it is our goal to define those differences. How the kidney responds to injury at an early stage can help in identifying potential therapeutic targets in the future.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08DK084305-03
Application #
8279443
Study Section
Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK)
Program Officer
Rankin, Tracy L
Project Start
2010-07-01
Project End
2015-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
3
Fiscal Year
2012
Total Cost
$152,269
Indirect Cost
$11,279
Name
University of California San Diego
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Nourbakhsh, Noureddin; Singh, Prabhleen (2014) Role of renal oxygenation and mitochondrial function in the pathophysiology of acute kidney injury. Nephron Clin Pract 127:149-52
Blantz, Roland C; Singh, Prabhleen (2014) Glomerular and tubular function in the diabetic kidney. Adv Chronic Kidney Dis 21:297-303
Singh, Prabhleen; Thomson, Scott C (2014) Salt sensitivity of tubuloglomerular feedback in the early remnant kidney. Am J Physiol Renal Physiol 306:F172-80
Thomson, Scott C; Kashkouli, Ali; Singh, Prabhleen (2013) Glucagon-like peptide-1 receptor stimulation increases GFR and suppresses proximal reabsorption in the rat. Am J Physiol Renal Physiol 304:F137-44
Singh, Prabhleen; Ricksten, Sven-Erik; Bragadottir, Gudrun et al. (2013) Renal oxygenation and haemodynamics in acute kidney injury and chronic kidney disease. Clin Exp Pharmacol Physiol 40:138-47
Singh, Prabhleen; Blantz, Roland C; Rosenberger, Christian et al. (2012) Aberrant tubuloglomerular feedback and HIF-1? confer resistance to ischemia after subtotal nephrectomy. J Am Soc Nephrol 23:483-93
Thomson, Scott C; Rieg, Timo; Miracle, Cynthia et al. (2012) Acute and chronic effects of SGLT2 blockade on glomerular and tubular function in the early diabetic rat. Am J Physiol Regul Integr Comp Physiol 302:R75-83
Blantz, Roland C; Singh, Prabhleen (2011) Analysis of the prerenal contributions to acute kidney injury. Contrib Nephrol 174:4-11
Singh, Prabhleen; Okusa, Mark D (2011) The role of tubuloglomerular feedback in the pathogenesis of acute kidney injury. Contrib Nephrol 174:12-21
Deng, Aihua; Arndt, Mary Ann K; Satriano, Joseph et al. (2010) Renal protection in chronic kidney disease: hypoxia-inducible factor activation vs. angiotensin II blockade. Am J Physiol Renal Physiol 299:F1365-73