Chronic kidney disease (CKD) is grave health problem in the U.S.A. and worldwide with unacceptably high morbidity and mortality. Disorders of mineral metabolism are ubiquitous and assume a central role in CKD in terms of contribution to its progression, complications, and mortality. Models of dysfunctional mineral metabolism in CKD have evolved over time and some effective interventions have indeed been developed but are still rather limited in terms of their ability to prevent or reverse these morbid disorders. Based on the current database including our own preliminary data, we present a model where Klotho deficiency is an early event in CKD followed by rise in fibroblast growth factor-23 (FGF23) and decline in vitamin D, which is then compounded by hyperparathyroidism and hyperphosphatemia. These disturbances aggravate each other resulting in a self-amplifying downward spiral that leads to numerous morbid consequences of mineral disturbance that ramifies into bone disease and cardiovascular complications. We propose to test our hypothesis utilizing not observational measurements, but an interventional approach to interrupt the vicious cycle rather than using primarily rodent models of CKD. First, we will restore normal Klotho expression by replacement therapy and look for retardation or arrest of progression and complications of kidney disease. Second, we will suppress endogenous FGF23 using an antagonistic peptide (C-terminal fragment of FGF23) that we discovered and verified in normal rodents. The read-out will be the same as that used for testing Klotho replacement therapy. Third, we will test several simple maneuvers that can potentially preserve or stimulate endogenous Klotho expression. Depending on the initial findings from these three sets of studies, we will consider designing combination therapy. Mineral disturbances in CKD is in dire need for novel models that encompass more of our database and most critically, definitive interventions that target the root of the problem. The proposed experiments serve dual purposes. It will prove or refute our hypothesis of the vicious cycle of Klotho, FGF23, vitamin D, parathyroid hormone, and phosphate. In addition, it will also lay the foundation of preclinical data to test the therapeutic potential of Klotho replacement and FGF23 antagonism.

Public Health Relevance

Chronic kidney disease is a formidable public healthy problem that impacts negatively on quality of life, survival, and health care costs but there is limited definitive therapy at present at our disposal. We constructed a model where abnormalities in two proteins called Klotho and Fibroblast Growth Factor-23 triggers a downhill spiral of a host of ill events in kidney disease. In this application, we aim to test this model and also devise novel ways to arrest this spiraling deterioration.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK091392-03
Application #
8451566
Study Section
Cellular and Molecular Biology of the Kidney Study Section (CMBK)
Program Officer
Kimmel, Paul
Project Start
2011-04-10
Project End
2016-03-31
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
3
Fiscal Year
2013
Total Cost
$333,722
Indirect Cost
$123,834
Name
University of Texas Sw Medical Center Dallas
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
800771545
City
Dallas
State
TX
Country
United States
Zip Code
75390
Fernández, Álvaro F; Sebti, Salwa; Wei, Yongjie et al. (2018) Disruption of the beclin 1-BCL2 autophagy regulatory complex promotes longevity in mice. Nature 558:136-140
Song, Parkyong; Zechner, Christoph; Hernandez, Genaro et al. (2018) The Hormone FGF21 Stimulates Water Drinking in Response to Ketogenic Diet and Alcohol. Cell Metab 27:1338-1347.e4
Chen, Gaozhi; Liu, Yang; Goetz, Regina et al. (2018) ?-Klotho is a non-enzymatic molecular scaffold for FGF23 hormone signalling. Nature 553:461-466
Shi, Mingjun; Flores, Brianna; Li, Peng et al. (2018) Effects of erythropoietin receptor activity on angiogenesis, tubular injury, and fibrosis in acute kidney injury: a ""U-shaped"" relationship. Am J Physiol Renal Physiol 314:F501-F516
Gazdhar, Amiq; Ravikumar, Priya; Pastor, Johanne et al. (2018) Alpha-Klotho Enrichment in Induced Pluripotent Stem Cell Secretome Contributes to Antioxidative Protection in Acute Lung Injury. Stem Cells 36:616-625
Rutkowski, Joseph M; Pastor, Johanne; Sun, Kai et al. (2017) Adiponectin alters renal calcium and phosphate excretion through regulation of klotho expression. Kidney Int 91:324-337
Neyra, Javier A; Hu, Ming Chang (2017) Potential application of klotho in human chronic kidney disease. Bone 100:41-49
Yao, H; Ma, Y; Hong, Z et al. (2017) Activating JAK2 mutants reveal cytokine receptor coupling differences that impact outcomes in myeloproliferative neoplasm. Leukemia 31:2122-2131
Hu, Ming Chang; Shi, Mingjun; Gillings, Nancy et al. (2017) Recombinant ?-Klotho may be prophylactic and therapeutic for acute to chronic kidney disease progression and uremic cardiomyopathy. Kidney Int 91:1104-1114
Lu, Xiang; Hu, Ming Chang (2017) Klotho/FGF23 Axis in Chronic Kidney Disease and Cardiovascular Disease. Kidney Dis (Basel) 3:15-23

Showing the most recent 10 out of 47 publications