Mast cells are required for the development of renal fibrosis in the rodent unilateral ureteral obstruction model
- 1 January 2012
- journal article
- research article
- Published by American Physiological Society in American Journal of Physiology-Renal Physiology
- Vol. 302 (1), F192-F204
- https://doi.org/10.1152/ajprenal.00562.2010
Abstract
Mast cells are associated with inflammation and fibrosis. Whether they protect against or contribute to renal fibrosis is unclear. Based on our previous findings that mast cells can express and secrete active renin, and that angiotensin (ANG II) is profibrotic, we hypothesized that mast cells play a critical role in tubulointerstitial fibrosis. We tested this hypothesis in the 14-day unilateral ureteral obstruction (UUO) model in rats and mast cell-deficient (MCD) mice (WBB6F1-W/Wv) and their congenic controls (CC). In the 14-day UUO rat kidney, mast cell number is increased and they express active renin. Stabilizing mast cells in vivo with administration of cromolyn sodium attenuated the development of tubulointerstitial fibrosis, which was confirmed by measuring newly synthesized pepsin-soluble collagen and blind scoring of fixed trichrome-stained kidney sections accompanied by spectral analysis. Fibrosis was absent in UUO kidneys from MCD mice unlike that observed in the CC mice. Losartan treatment reduced the fibrosis in the CC UUO kidneys. The effects of mast cell degranulation and renin release were tested in the isolated, perfused kidney preparation. Mast cell degranulation led to renin-dependent protracted flow recovery. This demonstrates that mast cell renin is active in situ and the ensuing ANG II can modulate intrarenal vascular resistance in the UUO kidney. Collectively, the data demonstrate that mast cells are critical to the development of renal fibrosis in the 14-day UUO kidney. Since renin is present in human kidney mast cells, our work identifies potential targets in the treatment of renal fibrosis.Keywords
This publication has 58 references indexed in Scilit:
- Mast cell renin and a local renin–angiotensin system in the airway: Role in bronchoconstrictionProceedings of the National Academy of Sciences of the United States of America, 2008
- Evidence for Abundant Presence of Chymase-Positive Mast Cells in the Kidneys of Patients with Immunoglobulin A Nephropathy: Effect of Combination Therapy with Prednisolone and Angiotensin II Receptor Blocker ValsartanHypertension Research, 2008
- TGF-β1 stimulates human AT1 receptor expression in lung fibroblasts by cross talk between the Smad, p38 MAPK, JNK, and PI3K signaling pathwaysAmerican Journal of Physiology-Lung Cellular and Molecular Physiology, 2007
- Angiotensin II type 1 receptor blockade attenuates TGF-β–induced failure of muscle regeneration in multiple myopathic statesNature Medicine, 2007
- Chemokine Receptor CX3CR1 Regulates Renal Interstitial Fibrosis after Ischemia-Reperfusion InjuryThe American Journal of Pathology, 2006
- Losartan, an AT1 Antagonist, Prevents Aortic Aneurysm in a Mouse Model of Marfan SyndromeScience, 2006
- Cardiac mast cell-derived renin promotes local angiotensin formation, norepinephrine release, and arrhythmias in ischemia/reperfusionJCI Insight, 2006
- Renal fibrosis: New insights into the pathogenesis and therapeuticsKidney International, 2006
- Why are angiotensin concentrations so high in the kidney?Current Opinion in Nephrology and Hypertension, 2004
- Mast cell infiltration and chemokine expression in progressive renal disease1Kidney International, 2003