Gq signaling causes glomerular injury by activating TRPC6

Wang, Liming; Jirka, Grant; Rosenberg, Paul B.; Buckley, Anne F.; Gómez, José A.; Fields, Timothy A.; Winn, Michelle P.; Spurney, Robert F.

doi:10.1172/jci76767

Cited by 61 publications

(82 citation statements)

References 86 publications

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“…42 Conversely, inactivation of TRPC6 using CRISPR/Cas9 methods reduces all aspects of kidney disease in the chronic PAN nephrosis model of FSGS in Sprague-Dawley rats, 25 and reduces glomerular disease caused by sustained angiotensin II infusions lasting up to three weeks in mice. 43,44 TRPC6 inactivation also reduced glomerulosclerosis in anti-GBM autoimmune | 777 HASSANZADEH KHAYYAT ET Al. glomerulonephritis in rats.…”

Section: Discussionmentioning

confidence: 99%

“…Mice selectively over‐expressing either wild‐type or mutant TRPC6 in podocytes similarly exhibit albuminuria, foot process effacement, and glomerulosclerosis . Conversely, inactivation of TRPC6 using CRISPR/Cas9 methods reduces all aspects of kidney disease in the chronic PAN nephrosis model of FSGS in Sprague‐Dawley rats, and reduces glomerular disease caused by sustained angiotensin II infusions lasting up to three weeks in mice . TRPC6 inactivation also reduced glomerulosclerosis in anti‐GBM autoimmune glomerulonephritis in rats .…”

Section: Discussionmentioning

confidence: 99%

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TRPC6 inactivation does not protect against diabetic kidney disease in streptozotocin (STZ)‐treated Sprague‐Dawley rats

2019

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Canonical transient receptor potential‐6 (TRPC6) channels have been implicated in the progression of several forms of kidney disease (1). While there is strong evidence that glomerular TRPC6 channels are dysregulated in diabetic nephropathy (DN), there is no consensus as to whether deletion or inactivation of TRPC6 is protective in animal models of DN. A previous study in Dahl salt‐sensitive rats suggests that TRPC6 knockout has a modest protective effect in streptozotocin (STZ)‐induced DN (2). In the present study, we examined whether inactivation of TRPC6 channels by CRISPR/Cas9 editing (Trpc6del/del rats) affects progression of STZ‐induced DN in Sprague‐Dawley rats. Wild‐type littermates (Trpc6wt/wt rats) were used as controls. We observed that a single injection of STZ resulted in severe hyperglycemia that was sustained over a 10‐week period, accompanied by a marked reduction in circulating C‐peptide, dyslipidemia, and failure to gain weight compared to vehicle‐treated animals. Those effects were equally severe in Trpc6wt/wt and Trpc6del/del rats. STZ treatment resulted in increased urine albumin excretion at 4, 8, and 10 weeks after injection, and this effect was equally severe in Trpc6wt/wt and Trpc6del/del rats. TRPC6 inactivation had no effect on blood urea nitrogen (BUN), plasma creatinine concentration, urine nephrin excretion, or kidney weight:body weight ratio measured 10 weeks after STZ injection. STZ treatment evoked modest and equivalent mesangial expansion in Trpc6wt/wt and Trpc6del/del rats. In summary, we observed no protective effect of TRPC6 inactivation on STZ‐induced DN in rats on the Sprague‐Dawley background.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

TRPC6 inactivation does not protect against diabetic kidney disease in streptozotocin (STZ)‐treated Sprague‐Dawley rats

2019

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“…Drugs that inhibit TRPC6: FK506 could ameliorate podocyte injury in T2DM, which may be linked to suppressed expressions of TRPC6 and NFAT [16] . Angiotensin receptor blockade and inhibition of local AngII production through angiotensin-converting enzyme inhibition prevented glucose-mediated intensified TRPC6 expression [8] .…”

Section: Effect Of Trpc Activation: Trpc6 Channel Stimulation Increasmentioning

confidence: 99%

TRPC 6 as a Molecular Target in Diabetic Nephropathy

Soni¹

2017

IJLSSR

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ABSTRACT-Transient Receptor Potential Canonical (TRPC6) assumes vital part in pathophysiology of DN and is up-regulated by angiotensin II, high glucose level, Transforming growth factor beta (TGFβ), and intercede podocyte damage in Diabetes Mellitus focusing on TRPC6 may reduce podocyte damage and proteinuria. From different investigation and proof gave by analyst and author work on pathophysiological part of TRPC 6 and the medications which modify or restrain TRPC6 or its downstream molecular target propose that TRPC6 is novel molecular target. Recently distinguished ROS/TRPC6 pathway will cover the best approach to new, reassuring restorative systems to target kidney ailments, especially Diabetic Nephropathy.

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“…calcineurin/NFAT pathway in podocytes (175), and activation of calcineurin increased TRPC6 expression in podocytes in a murine model of podocyte-specific constitutively active Gq a subunit (208). In another study, Eckel et al infused TRPC6-deficient and wild-type control mice with Ang II for 28 days.…”

Section: Trpc6 and Ros In Kidneymentioning

confidence: 99%

Canonical Transient Receptor Potential 6 Channel: A New Target of Reactive Oxygen Species in Renal Physiology and Pathology

Chaudhari

2016

Antioxidants & Redox Signaling

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Significance: Regulation of Ca 2+ signaling cascade by reactive oxygen species (ROS) is becoming increasingly evident and this regulation represents a key mechanism for control of many fundamental cellular functions. Canonical transient receptor potential (TRPC) 6, a member of Ca 2+ -conductive channel in the TRPC family, is widely expressed in kidney cells, including glomerular mesangial cells, podocytes, tubular epithelial cells, and vascular myocytes in renal microvasculature. Both overproduction of ROS and dysfunction of TRPC6 channel are involved in renal injury in animal models and human subjects. Although regulation of TRPC channel function by ROS has been well described in other tissues and cell types, such as vascular smooth muscle, this important cell regulatory mechanism has not been fully reviewed in kidney cells. Recent Advances: Accumulating evidence has shown that TRPC6 is a redox-sensitive channel, and modulation of TRPC6 Ca 2+ signaling by altering TRPC6 protein expression or TRPC6 channel activity in kidney cells is a downstream mechanism by which ROS induce renal damage. Critical Issues: This review highlights how recent studies analyzing function and expression of TRPC6 channels in the kidney and their response to ROS improve our mechanistic understanding of oxidative stress-related kidney diseases. Future Directions: Although it is evident that ROS regulate TRPC6-mediated Ca 2+ signaling in several types of kidney cells, further study is needed to identify the underlying molecular mechanism. We hope that the newly identified ROS/TRPC6 pathway will pave the way to new, promising therapeutic strategies to target kidney diseases such as diabetic nephropathy. Antioxid. Redox Signal. 25, 732-748.

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Gq signaling causes glomerular injury by activating TRPC6

Cited by 61 publications

References 86 publications

TRPC6 inactivation does not protect against diabetic kidney disease in streptozotocin (STZ)‐treated Sprague‐Dawley rats

TRPC6 inactivation does not protect against diabetic kidney disease in streptozotocin (STZ)‐treated Sprague‐Dawley rats

TRPC 6 as a Molecular Target in Diabetic Nephropathy

Canonical Transient Receptor Potential 6 Channel: A New Target of Reactive Oxygen Species in Renal Physiology and Pathology

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