Antifibrotic Effect of Tamoxifen in a Model of Progressive Renal Disease

Abstract

Tamoxifen, a selective estrogen receptor modulator, has antifibrotic properties; however, whether it can attenuate renal fibrosis is unknown. In this study, we tested the effects of tamoxifen in a model of hypertensive nephrosclerosis (chronic inhibition of nitric oxide synthesis with L-NAME). After 30 days, treated rats had significantly lower levels of albuminuria as well as lower histologic scores for glomerulosclerosis and interstitial fibrosis than untreated controls. Tamoxifen was renoprotective despite having no effect on the sustained, severe hypertension induced by L-NAME. Tamoxifen prevented the accumulation of extracellular matrix by decreasing the expression of collagen I, collagen III, and fibronectin mRNA and protein. These renoprotective effects associated with inhibition of TGF-b1 and plasminogen activator inhibitor-1, and with a significant reduction in a-smooth muscle actin-positive cells in the renal interstitium. Furthermore, tamoxifen abrogated IL-1b-and angiotensin-II-induced proliferation of fibroblasts from both kidney explants and from the NRK-49F cell line. Tamoxifen also inhibited the expression of extracellular matrix components and the production and release of TGF-b1 into the supernatant of these cells. In summary, tamoxifen exhibits antifibrotic effects in the L-NAME model of hypertensive nephrosclerosis, likely through the inhibition of TGF-b1, suggesting that it may have therapeutic use in CKD treatment.

Improved renal ischemia tolerance in females influences kidney transplantation outcomes

“…Moreover, renoprotection by estrogen is described in other forms of renal injury, including rat models of chronic allograft nephropathy (CAN) (15,24,25), age-related glomerular damage (29), and hypertensive nephrosclerosis (30). The role of estrogen receptors in this process remains a subject of debate.…”

Hypoxia: The Force that Drives Chronic Kidney Disease

“…[287][288][289][290][291] Tissue damage effected by these species is augmented by intermittent hypoxia reducing renal expression of antioxidants. 292 In addition, intermittent hypoxia induces the sympathetic nervous system to increase vascular resistance, downregulates expression of the kallikrein-kallistatin vasodilator Shelley Transforming growth factor β inhibition 446 Pro-fibrotic metalloproteinase inhibition 447 Anti-fibrotic metalloproteinase activation 447 Destabilization of renal Remote ischemic pre-conditioning [384][385][386][387][388][389][390] hypoxia-inducible factor Prolyl hydroxylase inhibition 244,448 von Hippel-Lindau protein inhibition 449 pathway, and activates the renal renin-angiotensin-aldosterone system to cause vasoconstriction. [293][294][295][296][297][298][299] Together these processes conspire to produce renal fibrosis and sustained hypertension and their associated means of reducing renal oxygenation ( figure 1).…”

Wnt4/β−Catenin Signaling in Medullary Kidney Myofibroblasts

“…In addition, because tamoxifen has been shown to affect fibrosis, we show that our tamoxifen treatment paradigm did not effect fibrotic response (Supplemental Figure 6). 32 To fate trace Wnt4 expressing cells, we measured baseline recombination 3 days after tamoxifen administration, to be sure that no further recombination would take place. 33,34 Wnt4 GCE/+ ;R26 tdTomato/+ mice were injected with tamoxifen 4 days after UUO injury and euthanized on day 7 and day 14. tdTomato+ cells were counted in coronal kidney sections of five mice at day 7 after UUO, which reflects the Wnt4+ cells present during days 4-7 after UUO ( Figure 5A and Supplemental Figure 7).…”