TRPC6 inactivation does not affect loss of renal function in nephrotoxic serum glomerulonephritis in rats, but reduces severity of glomerular lesions

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¹Department of Biology and Biochemistry, University of Houston, Houston, TX, USA.

Biochemistry and Biophysics Reports

|January 22, 2019

Abstract:

Canonical transient receptor potential-6 (TRPC6) channels have been implicated in a variety of chronic kidney diseases including familial and acquired forms of focal and segmental glomerulosclerosis (FSGS) and renal fibrosis following ureteral obstruction. Here we have examined the role of TRPC6 in progression of inflammation and fibrosis in the nephrotoxic serum (NTS) model of crescentic glomerulonephritis. This was assessed in rats with non-functional TRPC6 channels due to genomic disruption of an essential domain in TRPC6 channels (Trpc6 ^del/del rats) and wild-type littermates (Trpc6 ^wt/wt rats). Administration of NTS evoked albuminuria and proteinuria observed 4 and 28 days later that was equally severe in Trpc6 ^wt/wt and Trpc6 ^del/del rats. By 28 days, there were dense deposits of complement and IgG within glomeruli in both genotypes, accompanied by severe inflammation and fibrosis readily observed by standard histological methods, and also by increases in renal cortical expression of multiple markers (α-smooth muscle actin, vimentin, NLRP3, and CD68). Tubulointerstitial fibrosis appeared equally severe in Trpc6 ^wt/wt and Trpc6 ^del/del rats. TRPC6 inactivation did not protect against the substantial declines in renal function (increases in blood urea nitrogen, serum creatinine and kidney:body weight ratio) in NTS-treated animals, and increases in a urine maker of proximal tubule pathology (β2-macroglobulin) were actually more severe in Trpc6 ^del/del animals. By contrast, glomerular pathology, blindly scored from histology, and from renal cortical expression of podocin suggested a partial but significant protective effect of TRPC6 inactivation within the glomerular compartment, at least during the autologous phase of the NTS model.

Insights

Canonical transient receptor potential-6 (TRPC6) channel inactivation did not prevent kidney-wide inflammation or fibrosis in a rat model. However, TRPC6 disruption offered partial protection against glomerular injury in this model of crescentic glomerulonephritis.

Area of Science:

Nephrology
Molecular Biology
Immunology

Background:

Canonical transient receptor potential-6 (TRPC6) channels are linked to chronic kidney diseases like focal and segmental glomerulosclerosis and renal fibrosis.
The role of TRPC6 in the progression of crescentic glomerulonephritis, inflammation, and fibrosis remains incompletely understood.

Purpose of the Study:

To investigate the specific role of TRPC6 in the development and progression of kidney inflammation and fibrosis using the nephrotoxic serum (NTS) model.
To assess the protective effects of TRPC6 inactivation on glomerular and tubulointerstitial damage in crescentic glomerulonephritis.

Main Methods:

Utilized a nephrotoxic serum (NTS) model of crescentic glomerulonephritis in rats with genomic disruption of TRPC6 (Trpc6del/del) and wild-type littermates (Trpc6wt/wt).
Assessed kidney function, albuminuria, proteinuria, glomerular and tubulointerstitial histology, and expression of fibrosis and inflammation markers (α-smooth muscle actin, vimentin, NLRP3, CD68, podocin).

Main Results:

TRPC6 inactivation did not alter the severity of albuminuria, proteinuria, or tubulointerstitial fibrosis in NTS-treated rats.
Kidney function declined similarly in both genotypes, with more severe proximal tubule injury marker (β2-macroglobulin) in Trpc6del/del rats.
Histological scoring and podocin expression indicated a partial protective effect of TRPC6 inactivation specifically within the glomerular compartment.

Conclusions:

TRPC6 inactivation does not protect against overall kidney inflammation and fibrosis in the NTS model.
TRPC6 plays a role in glomerular pathology, suggesting potential therapeutic targeting within this specific kidney compartment.
Further research is needed to elucidate the precise mechanisms of TRPC6 in glomerular injury and repair.

Read full analysis

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