The Effects of TRPC6 Knockout in Animal Models of Kidney Disease

Abstract

Diseases that induce a loss of renal function affect a substantial portion of the world’s population and can range from a slight decline in the glomerular filtration rate or microalbuminuria to complete kidney failure. Kidney disorders can be acute or chronic, but any significant reduction in renal function is associated with increased all-cause morbidity and mortality, especially when the conditions become chronic. There is an urgent need for new therapeutic approaches to slow or halt the progression of kidney disease. One potential target of considerable interest is the canonical transient receptor potential-6 (TRPC6) channel. TRCP6 is a cationic channel with a significant permeability to Ca2+. It is expressed in several tissues, including in multiple cell types of the kidney in glomeruli, microvasculature, and tubules. Here, we will describe TRPC6 channels and their roles in signal transduction, with an emphasis on renal cells, and the studies implicating TRPC6 channels in the progression of inherited and acquired kidney diseases. We then describe studies using TRPC6 knockout mice and rats subjected to treatments that model human diseases, including nephrotic syndromes, diabetic nephropathy, autoimmune glomerulonephritis, and acute kidney injuries induced by renal ischemia and by obstruction of the urinary tract. TRPC6 knockout has been shown to reduce glomerular manifestations of disease in several of these models and reduces renal fibrosis caused by urinary tract obstruction. TRPC6 knockout has proven to be less effective at reducing diabetic nephropathy in mouse and rat models. We also summarize the implications of these studies for drug development.

Roles of TRP and PIEZO receptors in autoimmune diseases

“…A combined knockout of TRPC3, TRPC6, and TRPC7 reduced albuminuria and histological kidney injury. In the rat model, TRPC6 knockout had no significant protective effect against hyperglycaemia, albuminuria, histological kidney injury, blood urea nitrogen, or serum creatinine (Refs 6, 7).…”

“…In a rat model, the expression of TRPC6 in the glomerulus of rats treated with anti-glomerular basement membrane serum had significantly increased compared to rats treated with control serum. TRPC6 gene knockout could alleviate the pathological changes such as glomerular sclerosis; however, it does not reduce the related indexes such as total albuminuria, blood urea nitrogen and immunoglobulin (Refs 6, 69).…”

Reorganization and Suppression of Store-Operated Calcium Entry in Podocytes of Type 2 Diabetic Rats

“…The decisive contribution of TRPC6 channels to the pathological Ca 2+ signaling in the kidney has been demonstrated in many studies, especially in the studies of genetically inherited TRPC6 mutations that cause nephropathy. TRPC6 knockout or downregulation in podocytes was protective in several models of diabetes type 1 [ 10 , 18 , 19 ]. However, a recent publication has questioned the protective role of TRPC6 KO against DN in Sprague–Dawley rats injected with a high dose of streptozotocin (STZ) used to induce type 1 diabetes mellitus [ 20 ].…”

Reorganization and suppression of store-operated calcium entry in podocytes induced by diabetes type 2

“…TRPC6 channels form a relatively non-selective cation channel and could be activated by diacylglycerol (DAG) upon stimulation of G q/11 -coupled receptors linked to phospholipase Cβ (PLCβ), particularly angiotensin receptors [12][13][14]. TRPC6 knockout or downregulation in podocytes was protective in several models of diabetes type 1 [9,15,16]. However, a recent publication has questioned protective role of TRPC6 KO against DN in Sprague-Dawley rats injected with high dose of streptozotocin (STZ) used to induce type 1 diabetes mellitus [17].…”