The Multiple Roles of Fibroblast Growth Factor in Diabetic Nephropathy

Figures & data

Table 1 FGFs and Its Specific FGF Receptors

FGF Subfamily		FGF	Cofactor	FGF Receptor Activity
Paracrine Subfamily	FGF1 subfamily	FGF1	HS	All FGFRs
		FGF2		FGFR1c,3c>2c,1b,4
	FGF4 subfamily	FGF4		FGFR1c,2c>3c,4
		FGF5		FGFR1c,2c>3c,4
		FGF6		FGFR1c,2c>3c,4
	FGF7 subfamily	FGF3		FGFR2b>1b
		FGF7		FGFR2b>1b
		FGF10		FGFR2b>1b
		FGF22		FGFR2b>1b
	FGF8 subfamily	FGF8		FGFR3c>4>2c>1c≫3b
		FGF17		FGFR3c>4>2c>1c≫3b
		FGF18		FGFR3c>4>2c>1c≫3b
	FGF9 subfamily	FGF9		FGFR3c>2c>1c,3b≫4
		FGF16		FGFR3c>2c>1c,3b≫4
		FGF20		FGFR3c>2c>1c,3b≫4
Endocrine Subfamily	FGF19 subfamily	FGF19	β-Klotho	FGFR1c,2c,3c,4
		FGF21		FGFR1c,3c
		FGF23	α-Klotho	FGFR1c,2c,3c,4
Non-signal FGFs Subfamily	FGF11 subfamily	FGF11	Is not combined with FGFRs
		FGF12
		FGF13
		FGF14

Figure 1 An overview of the FGF signaling pathways. (A) Activation of FGFRs by FGFs via the paracrine pathway, mediated by HS cofactor. (B) Activation of FGFR by FGF-Klotho-FGFR ternary complex. The complex formation is regulated via the Endocrine pathway, mediated by Klotho protein cofactor. (C) Regulation of functioning of various signal transduction pathways such as growth and development in the human body by FGF-activated FGFR.

Figure 2 Pathological characteristics of DN. The first clinical manifestation of classical DN is the increase of urinary albumin excretion. The glomerular filtration rate is normal or even increased before urinary albumin excretion, but the glomerular filtration rate decreases after continuous urinary proteinuria, and eventually even developed into ESRD. And with increased urinary albumin excretion and an independent decline in glomerular filtration function, the patient’s risk of cardiovascular disease increases. According to the Tervaert classification of DN, the glomerular lesions of DN can be divided into four grades. I: Irregular thickening of the glomerular basement membrane was observed under an electron microscope. II: Mesangial hyperplasia and mesangial dilatation occur. III: There is at least one recognized tuberous sclerosis. IV: Advanced diabetic glomerulosclerosis of glomeruli.

Table 2 Ongoing Human Clinical Trials of FGF

Status	Study	Sponsor	Condition	Intervention	Phase
Recruiting	FGF23 and Angiotensin-(1-7) in Hypophosphatemia (GAP)	Wake Forest University Health Sciences	Hypophosphatemia; X-linked Hypophosphatemia; Renin-angiotensin System; Left Ventricular Hypertrophy	Diagnostic Test: Ang II and Ang-(1-7) Diagnostic Test: FGF23 and klotho	NA
Completed	Phosphate Intake’s Effect on the Skeletal System - Pilot	University of California, San Francisco	Healthy; Kidney Failure, Chronic	Behavioral: dietary phosphorus	NA
Completed	Modulation of Insulin Sensitivity by Betaine Upregulation of FGF21	UNC Nutrition Research Institute	Insulin Sensitivity	Dietary Supplement: Betaine Dietary Supplement: Dextrose	NA
Active, not recruiting	A Study of Experimental Medication BMS-986036 in Adults With Nonalcoholic Steatohepatitis (NASH) and Stage 3 Liver Fibrosis (FALCON 1)	Bristol-Myers Squibb	Liver Fibrosis; Nonalcoholic Fatty Liver Disease (NAFLD); Nonalcoholic Steatohepatitis	Drug: BMS-986036 (PEG-FGF21) Other: Placebo	Phase II
Recruiting	Effect of Weekly High-dose Vitamin D3 Supplementation on the Association Between Circulatory FGF-23 and A1c Levels in People With Vitamin D Deficiency: A Randomized Controlled 10-weeks Follow-up Trial.	Applied Science Private University	Diabetes Mellitus, Type 2 Kidney Diseases	Dietary Supplement: Soft gelatin capsules each contains 50,000 IU VD3 (cholecalciferol) equivalents to 1.25 mg.	NA
Unknown	Safety Study of Topical Human FGF-1 for Wound Healing	Phage Pharmaceuticals, Inc.	Diabetic Foot Ulcers	Drug: FGF-1141	Phase I
Completed	FGF-23 and Endothelial Dysfunction in Diabetic Proteinuric Patients	Gulhane School of Medicine	Proteinuria; Diabetic Nephropathy; Chronic Kidney Disease	Drug: Ramipril	Phase IV

Note: Sources: www.clinicaltrials.gov.

Abbreviation: NA, not applicable.

Figure 3 Effect of FGF1 on DN. FGF1 can ameliorate cell stress, inflammation, fibrosis and kidney injury.

Figure 4 The effect of FGF2 on EMT in renal tubular epithelial cells. The effect of Albuminuria, AGEs and FGF2 on PI3K/AKT pathway mediated expression of HPSE. HPSE can hydrolyze HSPG to generate HS fragments and inhibit the overexpression of multiligand proteoglycan-1, essential for FGF2 activation of. In addition, HPSE regulate the expression and activity of TGF-β.

Figure 5 The therapeutic effect of FGF21 on DN. Endoplasmic reticulum stress activates ATF4, which induce FGF21 expression. FGF21 protects kidney damage by activating multiple signaling pathways. PI3K/AKT pathway is shown to the left, STAT5 pathway in the middle and AMPK/SIRT1 on the right.