In Vivo Inhibition of TRPC6 by SH045 Attenuates Renal Fibrosis in a New Zealand Obese (NZO) Mouse Model of Metabolic Syndrome

Abstract

Metabolic syndrome is a significant worldwide public health challenge and is inextricably linked to adverse renal and cardiovascular outcomes. The inhibition of the transient receptor potential cation channel subfamily C member 6 (TRPC6) has been found to ameliorate renal outcomes in the unilateral ureteral obstruction (UUO) of accelerated renal fibrosis. Therefore, the pharmacological inhibition of TPRC6 could be a promising therapeutic intervention in the progressive tubulo-interstitial fibrosis in hypertension and metabolic syndrome. In the present study, we hypothesized that the novel selective TRPC6 inhibitor SH045 (larixyl N-methylcarbamate) ameliorates UUO-accelerated renal fibrosis in a New Zealand obese (NZO) mouse model, which is a polygenic model of metabolic syndrome. The in vivo inhibition of TRPC6 by SH045 markedly decreased the mRNA expression of pro-fibrotic markers (Col1α1, Col3α1, Col4α1, Acta2, Ccn2, Fn1) and chemokines (Cxcl1, Ccl5, Ccr2) in UUO kidneys of NZO mice compared to kidneys of vehicle-treated animals. Renal expressions of intercellular adhesion molecule 1 (ICAM-1) and α-smooth muscle actin (α-SMA) were diminished in SH045- versus vehicle-treated UUO mice. Furthermore, renal inflammatory cell infiltration (F4/80+ and CD4+) and tubulointerstitial fibrosis (Sirius red and fibronectin staining) were ameliorated in SH045-treated NZO mice. We conclude that the pharmacological inhibition of TRPC6 might be a promising antifibrotic therapeutic method to treat progressive tubulo-interstitial fibrosis in hypertension and metabolic syndrome.

Roles of TRP and PIEZO receptors in autoimmune diseases

“…Lupus kidney is the most common visceral lesion in SLE, and the severity of renal lesions directly affects the prognosis. Several studies have shown that TRPC6 gene inhibition can reduce pathological changes such as renal fibrosis (Refs 6, 69, 114, 115) and may delay the progression of lupus kidney. Furthermore, neuropsychiatric lupus erythematosus (NPSLE) is a group of serious complications related to a poor prognosis and high mortality caused by SLE lesions with nervous system involvement, resulting in neurological and/or psychiatric symptoms.…”

The Effects of TRPC6 Knockout in Animal Models of Kidney Disease

“…Thus, the selective TRPC6 inhibitor BI 749327 [ 89 ], and the pan-TRPC inhibitor 4-methyl-4-[3,5-bis(trifluoromethyl)-1H-pyrazol-1-yl]-1,2,3-thiadiazole-5-carbox anilide (BTP2) [ 64 ] have been observed to reduce renal fibrosis induced by UUO [ 64 , 89 ] well as cardiac fibrosis and hypertrophy in mice subjected to chronic pressure overload [ 89 ]. In addition, a structurally distinct TRPC6 inhibitor known as SH045 reduces renal fibrosis in an obesity model of metabolic syndrome [ 90 ]. Thus, TRPC6 knockout or inhibition in mice appears to have a non-trivial anti-fibrotic effect in at least two different tissues.…”

“…Studies using TRPC6 knockout animals support continuing drug discovery efforts that target TRPC6 channels directly or indirectly for therapy of kidney diseases. From a purely biological perspective, the strongest case for this class of drugs would be for people with familial nephrotic syndromes that are caused by one of the gain-of-function mutations of TRPC6, and it bears noting that SH045, which is a congener of the natural product (+)-larixol, is able to block those mutant TRPC6 variants [ 90 ]. Agents that block or suppress TRPC6 may also be effective in other genetic forms of FSGS, such as those that are associated with mutations in NPHS2 [ 23 ].…”

“…Based on the actions of putative serum “permeability factors” on TRPC6 channels in podocytes, including samples taken from patients, it is possible that TRPC6 inhibitors could be efficacious in people with primary FSGS [ 53 , 54 ], and knockout studies in rats support the concept of TRPC6 inhibition in adaptive forms of FSGS [ 50 ], commonly seen in patients with severe uncontrolled hypertension, reduced renal mass, or a markedly reduced number of functional nephrons. Based on studies in knockout mice, there is evidence that TRPC6 inhibition may be useful to reduce tubulointerstitial fibrosis, especially if it is caused by urinary tract obstruction [ 64 , 65 , 66 ], and, importantly, these conclusions are supported by pharmacological data [ 64 , 89 , 90 ]. Finally, and somewhat unexpectedly, the effects of TRPC6 knockout in diabetic kidney disease models in rodents have been disappointing [ 60 , 61 , 62 ].…”

Lanthanum hydroxide protects kidney through gut microbiota in a rat model of chronic kidney disease

“…Chronic kidney disease (CKD) is characterized by progressive damage to kidney parenchyma due to various causes, leading to significant kidney shrinkage and impaired function. 1 , 2 Affecting about 10% of the global population, CKD imposes substantial financial burdens, with the U.S. alone spending approximately 4.8 billion dollars annually. 3 Current treatments include dialysis, medication, and transplantation, each with its own limitations, such as high costs and donor scarcity.…”