Kidney Week

Abstract: SA-PO121

Overexpression of Hedgehog Interacting Protein in Renal Proximal Tubule Promotes Renal Tubulointerstitial Fibrosis in a Type I Diabetes Model

Session Information

• Diabetic Kidney Disease: Basic - III
  October 27, 2018 | Location: Exhibit Hall, San Diego Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Diabetic Kidney Disease

• 601 Diabetic Kidney Disease: Basic

Authors

• Chang, Shiao-Ying, CRCHUM, Universite de Montreal, Montreal, Quebec, Canada

Shiao-Ying Chang,

• Liao, Min-Chun, CRCHUM, Universite de Montreal, Montreal, Quebec, Canada

Min-Chun Liao,

• Zhao, Xin-Ping, CRCHUM, Universite de Montreal, Montreal, Quebec, Canada

Xin-Ping Zhao,

• Lo, Chao-Sheng, CRCHUM, Universite de Montreal, Montreal, Quebec, Canada

Chao-Sheng Lo,

• Chenier, Isabelle, CRCHUM, Universite de Montreal, Montreal, Quebec, Canada

Isabelle Chenier,

• Ingelfinger, Julie R., The New England Journal of Medicine, Boston, Massachusetts, United States

Julie R. Ingelfinger,

• Chan, John S.D., CRCHUM, Universite de Montreal, Montreal, Quebec, Canada

John S.D. Chan,

• Zhang, Shao-Ling, CRCHUM, Universite de Montreal, Montreal, Quebec, Canada

Shao-Ling Zhang,

Background

We previously reported (Sci. Report 2018) that renal hedgehog interacting protein (Hhip) gene expression is highly elevated in the kidneys of diabetic animal models and promotes the development of diabetic nephropathy. Since the molecular mechanism(s) of action in renal proximal tubular cells (RPTCs) is incompletely known, we examined the action of Hhip and its underlying mechanisms under diabetic conditions in RPTCs.

Methods

At 11 weeks of age male wild type (WT, C57BL6) and Hhip-transgenic (Tg) mice that specifically overexpressed Hhip in their RPTCs had diabetes induced with streptozotocin (STZ) (i.p., 50 mg/kg/day) for five consecutive days. Mice were euthanized 4 weeks after the STZ injection. Physiological parameters, kidney function (urinary albumin/creatinine ratio (ACR) and glomerular filtration rate (GFR)), renal morphology and molecular analysis of genes expression in renal proximal tubules were carried out. For in vitro studies, a rat immortalized RPTCs cell line (IRPTCs) was used.

Results

Non-diabetic Hhip-Tg mice were phenotypically indistinguishable from WT animals but had higher mRNA levels of fibrotic genes (TGFβ1, α-SMA) in their RPTCs. As compared to diabetic WT animals, diabetic Hhip-Tg mice exhibited pronounced tubulointerstitial fibrosis -- ‘tubulopathy’ features-- and increased renal heparanase (HPSE) [HPSE is a key player in renal fibrosis by mediating TGFβ1- related epithelial-mesenchymal transition (EMT) in tubular epithelial cells]. In vitro, recombinant Hhip (rHhip) dose-dependently stimulated HPSE expression and increased rat TGFβ1 promoter activity (pGL4.20/TGFβ1 (N-1016/+143)) in IRPTCs. Transient transfection of Hhip cDNA enhanced the expression of HPSE vs. control plasmid in IRPTCs. Finally, Hhip siRNA attenuated high glucose-stimulation of HPSE expression and/or TGFβ1- EMT signaling and ameliorated tubular fibrosis and apoptosis.

Conclusion

Overexpression of Hhip in RPTCs, which aggravates diabetes-related renal tubulointerstitial fibrosis, is mediated, at least in part, via elevated HPSE-TGFβ1-EMT signaling.

Funding

• Government Support - Non-U.S.