Crystals of calcium oxalate (CaOx), are major constituents of most urinary stones. They are also seen deposited in the kidneys of patients with primary or enteric hyperoxaluria. These crystals can be nephrotoxic, evoke an inflammatory response leading to fibrosis, loss of nephrons and possible renal failure. Tissue culture studies indicate that interactions between the crystals and renal cells produce reactive oxygen species (ROS), which appear to mediate many of the cellular responses. CaOx crystal deposition in rat kidneys leads to oxidant stress, is associated with the activation of renin-angiotensin system (RAS), and increases in the production of macromolecules such as osteopontin (OPN) that modulate crystal formation and their retention within the kidneys. Interstitial CaOx Crystal deposits are surrounded by monocytes and macrophages. Exposure of renal epithelial cells in culture to CaOx and CaP crystals is associated with increased production of the chemokine, monocyte chemoattractant protein-1 (MCP-1). Treatments with anti-oxidants, free radical scavengers, or angiotensin receptor blockers reduce CaOx crystal deposition in the kidneys of experimental animals. Based on these results, we hypothesize that "Renal crystal deposition induces inflammation in kidneys via the activation of renin-angiotensin system and NADPH oxidase, and production of reactive oxygen species. Reduction in ROS production will reduce the synthesis of macromolecules such as OPN and MCP-1 thereby reducing migration of monocytes and macrophages into the renal interstitium and subsequent inflammation and fibrosis." We propose to rigorously test this hypothesis in vivo using a rat model of renal CaOx crystal deposition and in vitro by exposing NRK52E and MDCK cells in culture to CaOx crystals, in order to define the precise series of molecular events that link intrarenal crystal deposition and eventual fibrosis. Results of such studies will improve the understanding of CaOx induced inflammation in nephrocalcinosis and nephrolithiasis. Studies may provide novel treatment targets and better treatment options to prevent the renal scarring that is associated with primary and enteric hyperoxaluria.

Public Health Relevance

Calcium oxalate crystal deposition in the kidneys is common in patients with primary and enteric hyperoxaluria, causing renal injury and inflammation. Enteric hyperoxaluria secondary to bariatric surgery is a serious emerging health problem. We are proposing to study the series of molecular events that link intrarenal crystal deposition and eventual fibrosis by exposing NRK52E and MDCK cells in culture to CaOx crystals and using a rat model of renal CaOx crystal deposition. Results of such studies will improve the understanding of CaOx induced inflammation and provide novel treatment targets and better treatment options to prevent the renal scarring that is associated with primary and enteric hyperoxaluria.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK078602-04
Application #
8223235
Study Section
Special Emphasis Panel (ZRG1-RUS-B (11))
Program Officer
Kirkali, Ziya
Project Start
2009-02-01
Project End
2014-01-31
Budget Start
2012-02-01
Budget End
2014-01-31
Support Year
4
Fiscal Year
2012
Total Cost
$312,297
Indirect Cost
$99,125
Name
University of Florida
Department
Pathology
Type
Schools of Medicine
DUNS #
969663814
City
Gainesville
State
FL
Country
United States
Zip Code
32611
Khan, Saeed R (2014) Reactive oxygen species, inflammation and calcium oxalate nephrolithiasis. Transl Androl Urol 3:256-276
Khan, Aslam; Wang, Wei; Khan, Saeed R (2014) Calcium oxalate nephrolithiasis and expression of matrix GLA protein in the kidneys. World J Urol 32:123-30
Tsuji, Hidenori; Shimizu, Nobutaka; Nozawa, Masahiro et al. (2014) Osteopontin knockdown in the kidneys of hyperoxaluric rats leads to reduction in renal calcium oxalate crystal deposition. Urolithiasis 42:195-202
Khan, Aslam; Byer, Karen; Khan, Saeed R (2014) Exposure of Madin-Darby canine kidney (MDCK) cells to oxalate and calcium oxalate crystals activates nicotinamide adenine dinucleotide phosphate (NADPH)-oxidase. Urology 83:510.e1-7
Khan, Saeed R; Joshi, Sunil; Wang, Wei et al. (2014) Regulation of macromolecular modulators of urinary stone formation by reactive oxygen species: transcriptional study in an animal model of hyperoxaluria. Am J Physiol Renal Physiol 306:F1285-95
Joshi, Sunil; Peck, Ammon B; Khan, Saeed R (2013) NADPH oxidase as a therapeutic target for oxalate induced injury in kidneys. Oxid Med Cell Longev 2013:462361
Khan, Saeed R (2013) Editorial comment. Urology 82:489.e7; discussion 489.e8
Khan, Saeed R; Rodriguez, Douglas E; Gower, Laurie B et al. (2012) Association of Randall plaque with collagen fibers and membrane vesicles. J Urol 187:1094-100
Khan, Saeed R; Glenton, Patricia A (2011) Experimentally induced hyperoxaluria in MCP-1 null mice. Urol Res 39:253-8
Zuo, Jian; Khan, Aslam; Glenton, Patricia A et al. (2011) Effect of NADPH oxidase inhibition on the expression of kidney injury molecule and calcium oxalate crystal deposition in hydroxy-L-proline-induced hyperoxaluria in the male Sprague-Dawley rats. Nephrol Dial Transplant 26:1785-96

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