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 #
1R01DK078602-01A2
Application #
7599376
Study Section
Special Emphasis Panel (ZRG1-RUS-B (11))
Program Officer
Rasooly, Rebekah S
Project Start
2009-02-01
Project End
2013-01-31
Budget Start
2009-02-01
Budget End
2010-01-31
Support Year
1
Fiscal Year
2009
Total Cost
$351,600
Indirect Cost
Name
University of Florida
Department
Pathology
Type
Schools of Medicine
DUNS #
969663814
City
Gainesville
State
FL
Country
United States
Zip Code
32611
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Bird, Victoria Y; Khan, Saeed R (2017) How do stones form? Is unification of theories on stone formation possible? Arch Esp Urol 70:12-27
O'Kell, Allison L; Grant, David C; Khan, Saeed R (2017) Pathogenesis of calcium oxalate urinary stone disease: species comparison of humans, dogs, and cats. Urolithiasis 45:329-336
Khan, Saeed R (2017) Histological aspects of the ""fixed-particle"" model of stone formation: animal studies. Urolithiasis 45:75-87
Joshi, Sunil; Wang, Wei; Khan, Saeed R (2017) Transcriptional study of hyperoxaluria and calcium oxalate nephrolithiasis in male rats: Inflammatory changes are mainly associated with crystal deposition. PLoS One 12:e0185009
Tsuji, Hidenori; Wang, Wei; Sunil, Joshi et al. (2016) Involvement of renin-angiotensin-aldosterone system in calcium oxalate crystal induced activation of NADPH oxidase and renal cell injury. World J Urol 34:89-95
Khan, Saeed R; Pearle, Margaret S; Robertson, William G et al. (2016) Kidney stones. Nat Rev Dis Primers 2:16008
Khan, Saeed R; Gambaro, Giovanni (2016) Role of Osteogenesis in the Formation of Randall's Plaques. Anat Rec (Hoboken) 299:5-7
Bonaccini, Laura; Karioti, Anastasia; Bergonzi, Maria Camilla et al. (2015) Effects of Salvia miltiorrhiza on CNS Neuronal Injury and Degeneration: A Plausible Complementary Role of Tanshinones and Depsides. Planta Med 81:1003-16
Joshi, Sunil; Clapp, William L; Wang, Wei et al. (2015) Osteogenic changes in kidneys of hyperoxaluric rats. Biochim Biophys Acta 1852:2000-12

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