FGF1ΔHBS delays the progression of diabetic nephropathy in late-stage type 2 diabetes mouse model by alleviating renal inflammation, fibrosis, and apoptosis

Qian Lin; Oscar Chen; John P Wise Jr; HongXue Shi; Kupper A Wintergerst; Lu Cai; Yi Tan

doi:10.1016/j.bbadis.2022.166414

FGF1^ΔHBS delays the progression of diabetic nephropathy in late-stage type 2 diabetes mouse model by alleviating renal inflammation, fibrosis, and apoptosis

Biochim Biophys Acta Mol Basis Dis. 2022 Aug 1;1868(8):166414. doi: 10.1016/j.bbadis.2022.166414. Epub 2022 Apr 18.

Authors

Qian Lin¹, Oscar Chen², John P Wise Jr², HongXue Shi³, Kupper A Wintergerst⁴, Lu Cai⁵, Yi Tan⁶

Affiliations

¹ Pediatic Research Institute, Departments of Pediatrics, Pharmacology & Toxicology, University of Louisville School of Medicine, Louisville, KY, USA. Electronic address: qian.lin@louisville.edu.
² Pediatic Research Institute, Departments of Pediatrics, Pharmacology & Toxicology, University of Louisville School of Medicine, Louisville, KY, USA.
³ Pediatic Research Institute, Departments of Pediatrics, Pharmacology & Toxicology, University of Louisville School of Medicine, Louisville, KY, USA; Department of Medicine, Columbia University Irving Medical Center, New York, NY, USA.
⁴ Pediatic Research Institute, Departments of Pediatrics, Pharmacology & Toxicology, University of Louisville School of Medicine, Louisville, KY, USA; Division of Endocrinology, Department of Pediatrics, University of Louisville, Louisville, KY, USA; Wendy L. Novak Diabetes Care Center, Louisville, KY, USA.
⁵ Pediatic Research Institute, Departments of Pediatrics, Pharmacology & Toxicology, University of Louisville School of Medicine, Louisville, KY, USA; Wendy L. Novak Diabetes Care Center, Louisville, KY, USA.
⁶ Pediatic Research Institute, Departments of Pediatrics, Pharmacology & Toxicology, University of Louisville School of Medicine, Louisville, KY, USA; Wendy L. Novak Diabetes Care Center, Louisville, KY, USA. Electronic address: yi.tan@louisville.edu.

Abstract

Elderly adults are at higher risk for developing diabetic complications including diabetic nephropathy (DN), contributing to excess morbidity and mortality in elderly individuals. A non-mitogenic variant of fibroblast growth factor 1 (FGF1^ΔHBS) was demonstrated to prevent DN in an early-stage (2-month-old) type 2 diabetes (T2D) mouse model. The present study aimed to investigate the potential therapeutic effects of FGF1^ΔHBS against the progression of renal dysfunction in a late-stage T2D mouse model with established DN. Nine-month-old db/db mice were administered FGF1^ΔHBS every other day for 3 months. db/db mice at 12-month-old without FGF1^ΔHBS treatment exhibited high blood glucose level and elevated urine albumin-to-creatinine ratio. FGF1^ΔHBS treatment effectively reversed hyperglycemia, delayed the development of renal dysfunction, and reduced kidney size and weight. Furthermore, FGF1^ΔHBS treatment significantly prevented the progression of renal morphologic impairment. FGF1^ΔHBS treatment demonstrated anti-inflammatory and anti-fibrotic effects, with significantly decreased protein levels of key pro-inflammatory cytokines and pro-fibrotic factors in kidney. Moreover, FGF1^ΔHBS treatment greatly decreased apoptosis of renal tubular cells, accompanied by significant downregulation of the proapoptotic protein and upregulation of the antiapoptotic protein and peroxisome proliferator-activated receptor α (PPARα) expression in kidney. Mechanistically, FGF1^ΔHBS treatment directly protected mouse proximal tubule cells against palmitate-induced apoptosis, which was abolished by PPARα inhibition. In conclusion, this study demonstrated that FGF1^ΔHBS delays the progression of renal dysfunction likely through activating PPARα to prevent renal tubule cell death in late-stage T2D, exhibiting a promising translational potential in treating DN in elderly T2D individuals by ameliorating renal inflammation, fibrosis and apoptosis.

Keywords: Apoptosis; Diabetic nephropathy; FGF1(ΔHBS); Fibrosis; Inflammation; Type 2 diabetes.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Apoptosis
Diabetes Mellitus, Type 2* / complications
Diabetic Nephropathies* / drug therapy
Diabetic Nephropathies* / metabolism
Disease Models, Animal
Fibroblast Growth Factor 1* / genetics
Fibroblast Growth Factor 1* / therapeutic use
Fibrosis
Humans
Inflammation / drug therapy
Inflammation / metabolism
Mice
PPAR alpha / metabolism

Substances

PPAR alpha
Fibroblast Growth Factor 1

Abstract

Publication types

MeSH terms

Substances

Grants and funding