Effects of TRPC6 Inactivation on Glomerulosclerosis and Renal Fibrosis in Aging Rats
Canonical transient receptor potential 6 (TRPC6) channels have been implicated in familial and acquired forms of focal and segmental glomerulosclerosis (FSGS) in patients and animal models, as well as in renal fibrosis following ureteral obstruction in mice. Aging also evokes declines in renal funct...
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MDPI AG
2021-04-01
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| Series: | Cells |
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| Online Access: | https://www.mdpi.com/2073-4409/10/4/856 |
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| author | Eun Young Kim Stuart E. Dryer |
| author_facet | Eun Young Kim Stuart E. Dryer |
| author_sort | Eun Young Kim |
| collection | DOAJ |
| description | Canonical transient receptor potential 6 (TRPC6) channels have been implicated in familial and acquired forms of focal and segmental glomerulosclerosis (FSGS) in patients and animal models, as well as in renal fibrosis following ureteral obstruction in mice. Aging also evokes declines in renal function owing to effects on almost every renal compartment in humans and rodents. Here, we have examined the role of TRPC6 in driving inflammation and fibrosis during aging in Sprague-Dawley rats. This was assessed in rats with non-functional TRPC6 channels owing to CRISPR-Cas9 deletion of a portion of the ankyrin repeat domain required for the assembly of functional TRPC6 channels (<i>Trpc6</i><sup>del/del</sup> rats). Wild-type littermates (<i>Trpc6</i><sup>wt/wt</sup> rats) were used as controls. Animals were evaluated at 2 months and 12 months of age. There was no sign of kidney disease at 2 months of age, regardless of genotype. However, by 12 months of age, all rats examined showed declines in renal function associated with albuminuria, azotemia and increased urine excretion of β2–microglobulin, a marker for proximal tubule pathology. These changes were equally severe in <i>Trpc6</i><sup>wt/wt</sup> and <i>Trpc6</i><sup>del/del</sup> rats. We also observed age-related increases in renal cortical expression of markers of fibrosis (α-smooth muscle actin and vimentin) and inflammation (NLRP3 and pro-IL−1β), and there was no detectable protective effect of TRPC6 inactivation. Tubulointerstitial fibrosis assessed from histology also appeared equally severe in <i>Trpc6</i><sup>wt/wt</sup> and <i>Trpc6</i><sup>del/del</sup> rats. By contrast, glomerular pathology, blindly scored from histological sections, suggested a significant protective effect of TRPC6 inactivation, but only within the glomerular compartment. |
| first_indexed | 2024-03-10T12:27:53Z |
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| institution | Directory Open Access Journal |
| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-10T12:27:53Z |
| publishDate | 2021-04-01 |
| publisher | MDPI AG |
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| series | Cells |
| spelling | doaj.art-4f27db9303a748d5b27b4b7ae586c0832023-11-21T14:52:15ZengMDPI AGCells2073-44092021-04-0110485610.3390/cells10040856Effects of TRPC6 Inactivation on Glomerulosclerosis and Renal Fibrosis in Aging RatsEun Young Kim0Stuart E. Dryer1Department of Biology and Biochemistry, University of Houston, Houston, TX 77204, USADepartment of Biology and Biochemistry, University of Houston, Houston, TX 77204, USACanonical transient receptor potential 6 (TRPC6) channels have been implicated in familial and acquired forms of focal and segmental glomerulosclerosis (FSGS) in patients and animal models, as well as in renal fibrosis following ureteral obstruction in mice. Aging also evokes declines in renal function owing to effects on almost every renal compartment in humans and rodents. Here, we have examined the role of TRPC6 in driving inflammation and fibrosis during aging in Sprague-Dawley rats. This was assessed in rats with non-functional TRPC6 channels owing to CRISPR-Cas9 deletion of a portion of the ankyrin repeat domain required for the assembly of functional TRPC6 channels (<i>Trpc6</i><sup>del/del</sup> rats). Wild-type littermates (<i>Trpc6</i><sup>wt/wt</sup> rats) were used as controls. Animals were evaluated at 2 months and 12 months of age. There was no sign of kidney disease at 2 months of age, regardless of genotype. However, by 12 months of age, all rats examined showed declines in renal function associated with albuminuria, azotemia and increased urine excretion of β2–microglobulin, a marker for proximal tubule pathology. These changes were equally severe in <i>Trpc6</i><sup>wt/wt</sup> and <i>Trpc6</i><sup>del/del</sup> rats. We also observed age-related increases in renal cortical expression of markers of fibrosis (α-smooth muscle actin and vimentin) and inflammation (NLRP3 and pro-IL−1β), and there was no detectable protective effect of TRPC6 inactivation. Tubulointerstitial fibrosis assessed from histology also appeared equally severe in <i>Trpc6</i><sup>wt/wt</sup> and <i>Trpc6</i><sup>del/del</sup> rats. By contrast, glomerular pathology, blindly scored from histological sections, suggested a significant protective effect of TRPC6 inactivation, but only within the glomerular compartment.https://www.mdpi.com/2073-4409/10/4/856TRPC6agingglomerulosclerosistubulointerstitial fibrosisalbuminuria |
| spellingShingle | Eun Young Kim Stuart E. Dryer Effects of TRPC6 Inactivation on Glomerulosclerosis and Renal Fibrosis in Aging Rats Cells TRPC6 aging glomerulosclerosis tubulointerstitial fibrosis albuminuria |
| title | Effects of TRPC6 Inactivation on Glomerulosclerosis and Renal Fibrosis in Aging Rats |
| title_full | Effects of TRPC6 Inactivation on Glomerulosclerosis and Renal Fibrosis in Aging Rats |
| title_fullStr | Effects of TRPC6 Inactivation on Glomerulosclerosis and Renal Fibrosis in Aging Rats |
| title_full_unstemmed | Effects of TRPC6 Inactivation on Glomerulosclerosis and Renal Fibrosis in Aging Rats |
| title_short | Effects of TRPC6 Inactivation on Glomerulosclerosis and Renal Fibrosis in Aging Rats |
| title_sort | effects of trpc6 inactivation on glomerulosclerosis and renal fibrosis in aging rats |
| topic | TRPC6 aging glomerulosclerosis tubulointerstitial fibrosis albuminuria |
| url | https://www.mdpi.com/2073-4409/10/4/856 |
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