TRPM7 contributes to progressive nephropathy

Abstract

TRPM7 belongs to the Transient Receptor Potential Melastatin family of ion channels and is a divalent cation-conducting ion channel fused with a functional kinase. TRPM7 plays a key role in a variety of diseases, including neuronal death in ischemia, cancer, cardiac atrial fibrillation, malaria invasion. TRPM7 is aberrantly over-expressed in lung, liver and heart fibrosis. It is also overexpressed after renal ischemia-reperfusion, an event that induces kidney injury and fibrosis. However, the role of TRPM7 in kidney fibrosis is unclear. Using the unilateral ureteral obstruction (UUO) mouse model, we examined whether TRPM7 contributes to progressive renal damage and fibrosis. We find that TRPM7 expression increases in UUO kidneys. Systemic application of NS8593, a known TRPM7 inhibitor, prevents kidney atrophy in UUO kidneys, retains tubular formation, and reduces TRPM7 expression to normal levels. Cell proliferation of both tubular epithelial cells and interstitial cells is reduced by NS8593 treatment in UUO kidneys, as are TGF-β1/Smad signaling events. We conclude that TRPM7 is upregulated during inflammatory renal damage and propose that pharmacological intervention targeting TRPM7 may prove protective in progressive kidney fibrosis.TRPM7 belongs to the Transient Receptor Potential (TRP) Melastatin family of ion channels, but is unique in that its ion channel domain is fused with a functional serine/threonine kinase 1 . TRPM7 was the first ion channel shown to conduct a range of divalent cations 2,3 , including physiologically essential divalent cations such as Ca 2+ , Mg 2+ , Zn 2+ , Ni 2+ , Mn 2+ , and Co 2+ . Ample evidence supports TRPM7 to be critical in regulating Mg 2+ homeostasis 1 and play a key role in a variety of diseases, including neuronal death in ischemia 4 , renal ischemia 5 , and cardiac atrial fibrillation 6 . TRPM7 is expressed ubiquitously in mammals, and is key in driving cell growth and proliferation, linking the protein to hyperproliferative diseases such cancer 1,7,8 and pulmonary, hepatic, and cardiac fibrosis 6,9-12 . Tissue fibrosis refers to a number of conditions that cause interstitial organ damage followed by inflammation and maladaptive wound healing eventually leading to fibrosis and chronic disease in the organ affected. TRPM7 overexpression leads to fibrosis through the TGF-β signaling pathway 9-11 . Recent in vitro data show that TRPM7 plays a pivotal role in progressive inflammatory and fibrotic disease by promoting excessive extracellular matrix (ECM) deposition 9 . It regulates proliferation and differentiation of fibroblasts 11 and proliferation and polarization of macrophages 13 as well as their Ca 2+ -dependent activation 14 . A recent study supports this hypothesis, as genetic suppression of TRPM7 in a kidney transplantation mouse model alleviated progressive inflammatory kidney fibrosis 15 .In the kidney, cell proliferation is a central response to injury that culminates in the development of fibrosis and renal failure. Unilateral ureteral obstruction (UUO) is a wide...

Mapping TRPM7 Function by NS8593

“…Genetic disruption of TRPM7 in cultured cells revealed that the TRPM7 channel is key to the homeostatic balance of divalent cations including Zn 2+ , Mg 2+ and Ca 2+ [ 14 , 22 , 23 , 24 , 25 , 26 ], cell motility [ 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 ], proliferation [ 1 , 23 , 24 , 35 , 36 , 37 ], differentiation [ 38 , 39 ], Ca 2+ signaling events [ 40 , 41 ] and an ever growing number of other cellular processes [ 5 , 6 , 7 , 8 , 9 , 10 , 11 ]. Pathophysiological implications of TRPM7 are widespread and include anoxic neuronal death [ 42 ], hypertension [ 43 , 44 ], neurodegenerative disorders [ 45 , 46 ], tissue fibrosis [ 47 , 48 , 49 , 50 ], tumour growth/progression [ 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 ] and abnormal immune responses [ 59 ]. Genetic association studies in humans revealed that point mutations in the TRPM7 gene cause a giant platelet disorder (macrothrombocytopenia) [ 60 ].…”

“…TRPM7 expression was also increased after renal ischemia-reperfusion leading to kidney injury and fibrosis [ 135 , 136 ]. Recently, Suzuki et al [ 49 ] investigated the unilateral ureteral obstruction (UUO) mouse model and observed that TRPM7 expression was elevated in UUO kidneys. Intraperitoneal injection of NS8593 (7 days; 5 mg/kg/day) prevented kidney atrophy in UUO kidneys, retained tubular formation, and reduced TRPM7 expression to normal levels.…”

“…Mechanistically, the authors suggested that TRPM7 affects tissue fibrosis via the TGF-β1/Smad network. The authors propose that pharmacological targeting of TRPM7 may be used to suppress kidney fibrosis [ 49 ].…”

On the Connections between TRPM Channels and SOCE

“…This channel-kinase symbiosis paired with its ubiquitous expression gives it a central and non-redundant role in cellular processes. Its pathophysiology is broad being linked to neurodegenerative disorders, hypertension, and tissue fibrosis and to atypical immune responses [ 120 , 121 , 122 , 123 , 124 , 125 , 126 , 127 ]. As versatile as the function of TRPM7 is, so is its regulation by a variety of internal and external cellular factors.…”

TRPM7 restrains plasmin activity and promotes transforming growth factor-β1 signaling in primary human lung fibroblasts

“…Interestingly, TRPM7 kinase directly phosphorylates SMAD-2 and enhances acute TGF-β1-induced SMAD-2 activation in isolated T-lymphocytes, offering a potential explanation for the positive effects of TRPM7 on TGF-β1-induced collagen expression observed in MRC5 cells (Romagnani et al 2017). Furthermore, TRPM7 promotes the development of heart and kidney fibrosis, pointing to a possible role of TRPM7 in signaling pathways leading to fibrotic processes (Du et al 2010;Rios et al 2020;Suzuki et al 2020).…”