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Knockout of TRPC6 promotes insulin resistance and exacerbates glomerular injury in Akita mice.

ABSTRACT: Gain-of-function mutations in TRPC6 cause familial focal segmental glomerulosclerosis, and TRPC6 is upregulated in glomerular diseases including diabetic kidney disease. We studied the effect of systemic TRPC6 knockout in the Akita model of type 1 diabetes. Knockout of TRPC6 inhibited albuminuria in Akita mice at 12 and 16 weeks of age, but this difference disappeared by 20 weeks. Knockout of TRPC6 also reduced tubular injury in Akita mice; however, mesangial expansion was significantly increased. Hyperglycemia and blood pressure were similar between TRPC6 knockout and wild-type Akita mice, but knockout mice were more insulin resistant. In cultured podocytes, knockout of TRPC6 inhibited expression of the calcium/calcineurin responsive gene insulin receptor substrate 2 and decreased insulin responsiveness. Insulin resistance is reported to promote diabetic kidney disease independent of blood glucose levels. While the mechanisms are not fully understood, insulin activates both Akt2 and ERK, which inhibits apoptosis signal regulated kinase 1 (ASK1)-p38-induced apoptosis. In cultured podocytes, hyperglycemia stimulated p38 signaling and induced apoptosis, which was reduced by insulin and ASK1 inhibition and enhanced by Akt or ERK inhibition. Glomerular p38 signaling was increased in TRPC6 knockout Akita mice and was associated with enhanced expression of the p38 gene target cyclooxygenase 2. These data suggest that knockout of TRPC6 in Akita mice promotes insulin resistance and exacerbates glomerular disease independent of hyperglycemia.

SUBMITTER: Wang L

PROVIDER: S-EPMC6696997 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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Knockout of TRPC6 promotes insulin resistance and exacerbates glomerular injury in Akita mice.

Wang Liming L Chang Jae-Hyung JH Buckley Anne F AF Spurney Robert F RF

Kidney international 20190201 2

Gain-of-function mutations in TRPC6 cause familial focal segmental glomerulosclerosis, and TRPC6 is upregulated in glomerular diseases including diabetic kidney disease. We studied the effect of systemic TRPC6 knockout in the Akita model of type 1 diabetes. Knockout of TRPC6 inhibited albuminuria in Akita mice at 12 and 16 weeks of age, but this difference disappeared by 20 weeks. Knockout of TRPC6 also reduced tubular injury in Akita mice; however, mesangial expansion was significantly increase ...[more]

PMID: 30665571

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Project description:ObjectiveThe dominant-negative P467L mutation in peroxisome proliferator activated receptor-? (PPAR?) was identified in insulin-resistant patients with hyperglycemia and lipodystrophy. In contrast, mice carrying the corresponding Pparg-P465L mutation have normal insulin sensitivity, with mild hyperinsulinemia. We hypothesized that murine Pparg-P465L mutation leads to covert insulin resistance, which is masked by hyperinsulinemia and increased pancreatic islet mass, to retain normal plasma glucose.Research design and methodsWe introduced in Pparg(P465L/+) mice an Ins2-Akita mutation that causes improper protein folding and islet apoptosis to lower plasma insulin.ResultsUnlike Ins2(Akita/+) littermates, male Pparg(P465L/+)Ins2(Akita/+) mice have drastically reduced life span with enhanced type 1 diabetes. Hyperglycemia in Ins2(Akita/+) females is mild. However, Pparg(P465L/+)Ins2(Akita/+) females have aggravated hyperglycemia, smaller islets, and reduced plasma insulin. In an insulin tolerance test, they showed smaller reduction in plasma glucose, indicating impaired insulin sensitivity. Although gluconeogenesis is enhanced in Pparg(P465L/+)Ins2(Akita/+) mice compared with Ins2(Akita/+), exogenous insulin equally suppressed gluconeogenesis in hepatocytes, suggesting that Pparg(P465L/+)Ins2(Akita/+) livers are insulin sensitive. Expression of genes regulating insulin sensitivity and glycogen and triglyceride contents suggest that skeletal muscles are equally insulin sensitive. In contrast, adipose tissue and isolated adipocytes from Pparg(P465L/+)Ins2(Akita/+) mice have impaired glucose uptake in response to exogenous insulin. Pparg(P465L/+)Ins2(Akita/+) mice have smaller fat depots composed of larger adipocytes, suggesting impaired lipid storage with subsequent hepatomegaly and hypertriglyceridemia.ConclusionsPPARg-P465L mutation worsens hyperglycemia in Ins2(Akita/+) mice primarily because of adipose-specific insulin resistance and altered storage function. This underscores the important interplay between insulin and PPAR? in adipose tissues in diabetes.

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Knockout of TRPC6 promotes insulin resistance and exacerbates glomerular injury in Akita mice.

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Knockout of TRPC6 promotes insulin resistance and exacerbates glomerular injury in Akita mice.

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