Cysteamine Modulates Oxidative Stress and Blocks Myofibroblast Activity in CKD

Abstract

Therapy to slow the relentless expansion of interstitial extracellular matrix that leads to renal functional decline in patients with CKD is currently lacking. Because chronic kidney injury increases tissue oxidative stress, we evaluated the antifibrotic efficacy of cysteamine bitartrate, an antioxidant therapy for patients with nephropathic cystinosis, in a mouse model of unilateral ureteral obstruction. Fresh cysteamine (600 mg/kg) was added to drinking water daily beginning on the day of surgery, and outcomes were assessed on days 7, 14, and 21 after surgery. Plasma cysteamine levels showed diurnal variation, with peak levels similar to those observed in patients with cystinosis. In cysteamine-treated mice, fibrosis severity decreased significantly at 14 and 21 days after unilateral ureteral obstruction, and renal oxidized protein levels decreased at each time point, suggesting reduced oxidative stress. Consistent with these results, treatment of cultured macrophages with cysteamine reduced cellular generation of reactive oxygen species. Furthermore, treatment with cysteamine reduced a-smooth muscle actin-positive interstitial myofibroblast proliferation and mRNA levels of extracellular matrix proteins in mice and attenuated myofibroblast differentiation and proliferation in vitro, but did not augment TGF-b signaling. In a study of renal ischemia reperfusion, cysteamine therapy initiated 10 days after injury and continued for 14 days decreased renal fibrosis by 40%. Taken together, these data suggest previously unrecognized antifibrotic actions of cysteamine via TGF-b-independent mechanisms that include oxidative stress reduction and attenuation of the myofibroblast response to kidney injury and support further investigation into the potential benefit of cysteamine therapy in the treatment of CKD.

Renal Allograft Fibrosis: Biology and Therapeutic Targets

“…Various complement components are involved in renal allograft damage and fibrosis (81)(82)(83). For example, complement promotes fibrosis and reduces allograft survival in proteinuric and non-proteinuric models of renal fibrosis and kidney transplantation (84)(85)(86)(87)(88)(89). Several clinical trials targeting the complement system are ongoing in various renal diseases, including renal allografts (81).…”

“…Several molecules were proposed to be involved in the profibrotic switch of fibroblasts (or pericytes) during renal fibrosis, including the Wnt signaling pathway (e.g., Wnt4, LRP-6, and DKK-1) (183,184), oxidative stress and NADPH oxidase (39,88,185), integrins including aV integrin (186), Rheb/mTORC1 signaling (187) as well as lipid mediators, including prostaglandins and their receptors like EP4 (188,189), prostacyclins (190), or lipoxins (191,192).…”

Induction of oxidative stress by anticancer drugs in the presence and absence of cells

“…In the present study, cell staining with CellROX ® Green reagent was performed in order to directly measure the intracellular ROS formation (16)(17)(18). CellROX ® reagent is a fluorogenic probe used for measuring oxidative stress in cells and exhibits bright-green photostable fluorescence upon oxidation by ROS.…”

Antifibrotic Therapy

“…Changes in practice patterns leading to the decrease in early starts were influenced by well designed, patientoriented research informing conversations with patients around the timing of and need for renal replacement therapy. [9][10][11][12][13][14][15][16][17][18][19] The knowledge gained from these studies and others about the pros and cons of therapy options, including maximum conservative management, should be incorporated into patient-centered, age-relevant decision aids, a tool that is successful in helping patients understand the effect of various options on their healthcare goals and personal priorities. 20,21 Unfortunately, many elderly patients do not decide whether to pursue renal replacement therapy while they are in calm, controlled preemptive settings.…”