TRPC Channels in Proteinuric Kidney Diseases

Hall, Gentzon; Wang, Liming; Spurney, Robert F.

doi:10.3390/cells9010044

Cited by 52 publications

(56 citation statements)

References 171 publications

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“…The precise molecular target of TH1177 in this study is not established and actions on cation channels other than TTCC are entirely possible, including effects on Stim/Orai pathways and TRP channels [10], and these could be pivotal in the biological effects seen. In particular, TRPC family channels are implicated in glomerular pathology [11] and may be influenced by TH1177. Like all channel inhibitors, TH1177 is not 100% specific and likely can alter multiple ion currents.…”

Section: Discussionmentioning

confidence: 99%

Ion-Channel modulator TH1177 reduces glomerular injury and serum creatinine in chronic mesangial proliferative disease in rats

et al. 2020

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Background: T-type calcium channels (TTCC) are involved in mesangial cell proliferation. In acute thy-1 nephritis in the rat TTCC inhibition reduces glomerular damage and cell proliferation. This work is extended here by a study of the non-selective TTCC inhibitor TH1177 in a chronic model of proliferative glomerulonephritis (GN) including late treatment starting after the initial inflammation has resolved. The objective was to determine the effects of TH1177 in a model of chronic mesangioproliferative renal disease. Methods: Chronic GN was induced in WKY rats by unilateral nephrectomy (day − 7) followed by day 0 injection of Ox7 thy-1 mAb. Treatment with TH1177 (10-20 mg/Kg daily IP) was started on day 2 (early treatment) or on day 14 (late treatment) and compared to vehicle-treated controls until sacrifice at day 42. Glomerular disease was assessed with a damage score, fibrosis assay, cellular counts and renal function measured by serum creatinine. Results: Treatment with TH11777 was associated with reduced serum creatinine, less glomerular damage, reduced fibrosis and reduced glomerular cellularity. The results for early and late TH1177 treatments were essentially the same and differed significantly from vehicle. Conclusions: The ion-channel modulator TH1177 is capable of improving glomerular outcome in chronic rat GN even when treatment starts 14 days after initiation of the disease. These data are discussed in the context of the possible targets of TH1177 including TTCC, TRP family, Stim/Orai group and other cation channels. The work supports the use of genetic models to examine the roles of individual cation channels in progressive glomerulonephritis to further define the targets of TH1177.

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Section: Discussionmentioning

confidence: 99%

Ion-Channel modulator TH1177 reduces glomerular injury and serum creatinine in chronic mesangial proliferative disease in rats

et al. 2020

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“…TPRC6 plays multiple roles in activating RhoA and Rac1 in response to mechanical stress and influences the function of nephrin, podocin, CD2AP and synaptopodin by regulating intracellular calcium [ 138 ]. TPRC6 mutations have also been noted in several cases of congenital FSGS [ 75 , 139 , 140 , 141 ].…”

Section: Structural Regulation Of Actin Dynamics In Podocytesmentioning

confidence: 99%

Regulation of the Actin Cytoskeleton in Podocytes

Blaine

Dylewski

2020

Cells

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Podocytes are an integral part of the glomerular filtration barrier, a structure that prevents filtration of large proteins and macromolecules into the urine. Podocyte function is dependent on actin cytoskeleton regulation within the foot processes, structures that link podocytes to the glomerular basement membrane. Actin cytoskeleton dynamics in podocyte foot processes are complex and regulated by multiple proteins and other factors. There are two key signal integration and structural hubs within foot processes that regulate the actin cytoskeleton: the slit diaphragm and focal adhesions. Both modulate actin filament extension as well as foot process mobility. No matter what the initial cause, the final common pathway of podocyte damage is dysregulation of the actin cytoskeleton leading to foot process retraction and proteinuria. Disruption of the actin cytoskeleton can be due to acquired causes or to genetic mutations in key actin regulatory and signaling proteins. Here, we describe the major structural and signaling components that regulate the actin cytoskeleton in podocytes as well as acquired and genetic causes of actin dysregulation.

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“…Insulin mediates AMPK regulation through transient receptor potential canonical channel 6 (TRPC6) activation [99]. TRPC6 is a nonselective Ca 2+ channel protein that is implicated in the pathophysiology of kidney diseases [100]. In diabetic nephropathy, TRPC6 is upregulated, suggesting a putative role of TRPC6 expression in the progression of diabetic nephropathy pathology.…”

Section: Ampk and Renal Glucose Metabolismmentioning

confidence: 99%

Critical Role for AMPK in Metabolic Disease-Induced Chronic Kidney Disease

Juszczak

Caron

Mathew

et al. 2020

IJMS

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Chronic kidney disease (CKD) is prevalent in 9.1% of the global population and is a significant public health problem associated with increased morbidity and mortality. CKD is associated with highly prevalent physiological and metabolic disturbances such as hypertension, obesity, insulin resistance, cardiovascular disease, and aging, which are also risk factors for CKD pathogenesis and progression. Podocytes and proximal tubular cells of the kidney strongly express AMP-activated protein kinase (AMPK). AMPK plays essential roles in glucose and lipid metabolism, cell survival, growth, and inflammation. Thus, metabolic disease-induced renal diseases like obesity-related and diabetic chronic kidney disease demonstrate dysregulated AMPK in the kidney. Activating AMPK ameliorates the pathological and phenotypical features of both diseases. As a metabolic sensor, AMPK regulates active tubular transport and helps renal cells to survive low energy states. AMPK also exerts a key role in mitochondrial homeostasis and is known to regulate autophagy in mammalian cells. While the nutrient-sensing role of AMPK is critical in determining the fate of renal cells, the role of AMPK in kidney autophagy and mitochondrial quality control leading to pathology in metabolic disease-related CKD is not very clear and needs further investigation. This review highlights the crucial role of AMPK in renal cell dysfunction associated with metabolic diseases and aims to expand therapeutic strategies by understanding the molecular and cellular processes underlying CKD.

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TRPC Channels in Proteinuric Kidney Diseases

Cited by 52 publications

References 171 publications

Ion-Channel modulator TH1177 reduces glomerular injury and serum creatinine in chronic mesangial proliferative disease in rats

Ion-Channel modulator TH1177 reduces glomerular injury and serum creatinine in chronic mesangial proliferative disease in rats

Regulation of the Actin Cytoskeleton in Podocytes

Critical Role for AMPK in Metabolic Disease-Induced Chronic Kidney Disease

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