[GW28-e0960]

Seipin deficiency causes renal injury and reversed both by adipose tissue transplantation and leptin respectively in mice

Xuejing Liu Wei Huang
Institute of Cardiovascular Sciences and Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, Peking University Health Science Center, Beijing, 100191, China.

Objectives: Seipin deficiency is responsible for type 2 Berardinelli–Seip Congenital lipodystrophy (BSCL2) with severe loss of adipose tissue (AT), hyperlipidemia, insulin resistance (IR) and hepatic steatosis. Some patients with Seipin deficiency were reported died due to the renal failure. However, the function of Seipin in kidney was poorly understood. We supposed loss of fat played important role in the renal injury. Here in this study we investigated the effects of Seipin deficiency on renal injury and used two treatments to improve the renal injury.
Methods: 3-month-old Seipin^−/−(SKO) and wild-type (WT) mice were used in this study. The body weight, 24h urinary albumin excretion (UAE) and creatinine clearance were detected. For improve the renal injury, AT were transplanted to SKO mice (SKO-AT) for 3 months or SKO mice were injected by i.p. with leptin (SKO-Leptin) for 14 days respectively. Renal relative parameters, plasma leptin and adiponectin levels were studied. We evaluated glucose homeostasis and relevant genes expressions as well.
Results: Seipin mRNA expression levels in WT mice were higher in AT and testicles, and could also be found in kidney, which is mainly expression in glomeruli. SKO groups showed higher body weight, food intake and polyuria. Increased kidney weight/tibia length, 24 hours’ urinary excretion of Na⁺, K⁺, Cl^-, Ca²⁺, UAE, creatinine clearance, surface areas of glomerulus and mesangial were also increased compared with WT control groups. A few glomerular lipids depositions and disappeared brush border of renal tubule were observed in SKO groups. Electron microscopy revealed moderate mesangial proliferation and segmental effacement of podocyte foot processes in SKO mice. SKO mice showed delayed glucose clearance, IR and decreased plasma leptin and adiponectin levels. Real-time PCR revealed genes in water reabsorption like aquaporin1(AQP1), aquaporin7(AQP7) and vasopressin receptor 2 (V2R) were significantly lower in SKO mice than that in WT mice. Genes involved in salt reabsorption such as Sodium-potassium-chloride cotransporter 2(NKCC2), Epithelial sodium channel (Scnn1α, Scnn1β, Scnn1γ) Sodium-potassium pump/Na⁺-K⁺-ATPase (Atp1a1) were decreased in SKO mice as well. After the transplantation of AT, plasma leptin levels increased in SKO mice. The glomerular hyperfiltration and plasma glucose tolerance were improved. The remarkable reduction of UAE, glomerular and mesangial surface area were observed as well. Then we treated SKO mice with leptin. The renal injury and IR were recovered. Some genes expressions involved in reabsorption (AQP1, V2R, NKCC2, Scnn1α, Scnn1β, Scnn1γ, Atp1a1) were reaching to normal levels.
Conclusions: In our study, we first noticed that the renal injury in SKO mice which improved by transplantation of the AT or leptin treatment. It suggested lack of AT was responsible to renal injury in SKO mice. AT transplantation and leptin could be two effective treatments for renal injury in Seipin deficiency.