Empagliflozin alleviates podocytopathy and enhances glomerular nephrin expression in db/db diabetic mice

doi:10.4239/wjd.v11.i12.596

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World Journal of Diabetes

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World J Diabetes. Dec 15, 2020; 11(12): 596-610
Published online Dec 15, 2020. doi: 10.4239/wjd.v11.i12.596

Table 1 Body weight and fat mass in db/db and db/+ mice

Parameter	Age in wk	Group
		*Non-diabetic db/+* mice (n = 9)**	*db/db* diabetic mice
		*Non-diabetic db/+* mice (n = 9)**	Vehicle (n = 10)	EMPA (n = 9)
Body weight (g)	8	26.8 (25.0-31.1)	37.1 (32.1–41.6)^b	37.4 (28.5–41.5)^b
	12	26.2 (23.5–28.2)	37.5 (35.8–40.5)^b	46.2 (38.8–53.0)^b^,^c
	16	24.8 (21.6–27.7)^e	37.8 (34.3–40.4)^b	52.6 (42.5–62.2)^b^,^c^,^f
Fat mass (g)	8	3.1 (1.9–4.1)	18.3 (16.2–22.5)^a	18.4 (13.5–20.6)^b
	12	2.7 (1.9–3.3)	19.5 (17.0–22.7)^b	25.3 (21.7–30.9)^b^,^c
	16	2.7 (2.1–4.5)	19.6 (17.4–22.7)^b	28.0 (22.2–35.3)^a^,^d^,^e
Fat mass (%)	8	11.4 (8.5–16.1)	50.6 (46.6–55.3)^b	49.3 (46.8–50.0)^b
	12	10.7 (8.1–12.4)	52.5 (45.2–57.0)^b	55.5 (51.5–58.3)^b
	16	11.7 (7.6–13.2)	55.0 (42.5–62.8)^b	53.4 (49.1–56.7)^b

^aP< 0.01 vs non–diabetic control (db/+ mice, Mann-Whitney U-test).

^bP< 0.001 vs non–diabetic control (db/+ mice, Mann-Whitney U-test).

^cP< 0.01 vs placebo (Mann-Whitney U-test).

^dP< 0.001 vs placebo (Mann-Whitney U-test).

^eP< 0.01 vs wk 8 and 12 (ANOVA-χ² test).

^fP < 0.001 vs wk 8 and 12 (ANOVA-χ² test). Data are presented as medians (min–max values). EMPA: Empagliflozin.

Table 2 Plasma biochemistry in db/+ and db/db mice

Parameter	Age in wk	Group
		*Non-diabetic db/+* mice (n = 9)**	*Diabetic db/db* mice**
		*Non-diabetic db/+* mice (n = 9)**	Vehicle (n = 10)	EMPA (n = 9)
Glucose (mmoL/L)	8	9.50 (5.10–11.4)	28.5 (16.8–40.1)^b	23.1 (15.3–35.4)^b
	12	9.20 (6.10–9.50)	30.4 (22.7–48.0)^b	16.3 (13.6–20.7)^b^,^d^,^e
	16	9.50 (8.50–12.2)	32.7 (22.5–53.1)^b	16.1 (9.9–23.6)^b^,^d^,^e
Fructosamine (µmoL/L)	8	237 (217–249)	456 (424–511)^b	480 (425–579)^b
Fructosamine (µmoL/L)	16	239 (222–296)	622 (524–672)^b^,^f	468 (341–491)^b^,^c^,^e
Glycated albumin (µmoL/L)	8	107 (103–127)	227 (206–239)^b	235 (217–261)^b
Glycated albumin (µmoL/L)	16	117 (109–133)	283 (252–349)^b^,^f	210 (166–245)^b^,^c^,^e
Total cholesterol (mmoL/L)	8	2.76 (1.80–3.96)	2.72 (1.48–4.86)	2.76 (1.60–4.05)
Total cholesterol (mmoL/L)	16	2.37 (1.98–2.97)	3.57 (1.68–4.86)^e	4.05 (2.10–5.22)^e
HDL-cholesterol (mmoL/L)	8	1.17 (0.50–1.62)	1.20 (0.51–2.01)	1.40 (0.93–1.89)
HDL-cholesterol (mmoL/L)	16	1.26 (0.45–1.80)	1.50 (0.48–2.19)	2.31 (1.05–2.88)^e
LDL-cholesterol (mmoL/L)	8	1.32 (0.81–2.10)	1.02 (0.84–2.72)	1.07 (0.84–2.60)
LDL-cholesterol (mmoL/L)	16	0.81(0.75–1.11)^f	0.81 (0.72–1.14)	1.05 (0.60–1.41)
Triglycerides (mmoL/L)	8	1.74 (0.90–2.70)	1.14 (0.51–2.30)	1.25 (0.87–2.30)
Triglycerides (mmoL/L)	16	1.35 (0.81–2.58)	1.79 (1.17–3.54)^e	1.77 (1.29–3.87)^e
Creatinine (µmoL/L)	8	67.0 (47.0–78.0)	76.4 (70.2–84.2)	70.5 (54.0–82.2)
	12	68.6 (48.5–74.5)	76.5 (64.5–100.5)^a	74.7 (46.2–85.8)^a
	16	61.8 (54.0–71.7)	75.6 (63.9–89.4)^a	81.3 (55.8–91.2)^a
Uric acid (µmoL/L)	8	273 (104–420)	173 (143–341)	281 (165–507)
Uric acid (µmoL/L)	16	235 (159–271)	170 (143–187)	204 (179-242)

^aP < 0.01 vs non-diabetic control (db/+ mice, Mann-Whitney U-test).

^bP < 0.001 vs non-diabetic control (db/+ mice, Mann-Whitney U-test).

^cP < 0.01 vs placebo db/db group (Mann-Whitney U-test).

^dP < 0.001 vs placebo db/db group (Mann-Whitney U-test).

^eP < 0.05 vs placebo db/db group (Mann-Whitney U-test).

^fP < 0.01 compared with wk 8 (Wilcoxon test). Data are presented as medians (min–max values). EMPA: Empagliflozin.

Table 3 Plasma levels of leptin and insulin in db/+ and db/db mice

Hormone	Age in wk	Group
		*Non-diabetic db/+* mice (n = 9)**	*Diabetic db/db* mice**
		*Non-diabetic db/+* mice (n = 9)**	Vehicle (n = 10)	EMPA (n = 9)
Leptin (ng/mL)	8	3.3 (1.4–6.54)	97.1 (53.2–114.4)^b	93.4 (80.8–133.1)^b
Leptin (ng/mL)	16	3.8 (1.5–6.3)	90.0 (21.2–151.4)^b	136.4 (53.0–171.2)^b^,^c^,^d
Insulin (ng/mL)	8	5.6 (3.4–18.0)	25.6 (11.5–45.2)^b	21.2 (10.8–40.8)^b
Insulin (ng/mL)	16	10.0 (2.1–22.2)	22.1 (9.8–33.2)^a	20.8 (6.0–56.7)^a
Glucagon (ng/mL)	8	370 (250–2670)	660 (190–2760)	450 (290–2180)
Glucagon (ng/mL)	16	370 (150–2120)	605 (260–2960)	390 (240–860)

^aP < 0.01 vs non-diabetic control (db/+ mice, Mann-Whitney U-test).

^bP < 0.001 vs non-diabetic control (db/+ mice, Mann-Whitney U-test).

^cP < 0.05 vs placebo (Mann-Whitney U-test).

^dP < 0.05 vs wk 8 (Wilcoxon test). Data are presented as medians (min–max values). EMPA: Empagliflozin.

Table 4 Renal structural parameters in db/+ and db/db mice

Parameter	Group
	*Non-diabetic db/+* mice (n = 9)**	*Diabetic db/db* mice**
	*Non-diabetic db/+* mice (n = 9)**	Vehicle (n = 10)	EMPA (n = 9)
Mesangium, fractional volume (%)	14.4 (9.8–18.5)	38.6 (34.5–42.7)^a	25.5 (20.4–35.8)^d
Capillaries, fractional volume (%)	31.3 (28.9–38.7)	34.6 (30.9–36.1)	33.3 (29.5–37.0)
GBM, mean width (nm)	135 (116–157)	163 (135–203)^a	139 (116–225)^b
Podocyte FPs, mean width (nm)	220 (191–242)	372 (299–426)^a	203 (162–317)^c
Podocyte FPs (N_A, nm^–1)	3.39 (3.00–3.79)	2.73 (1.92–3.51)^a	3.31 (2.32–4.18)^b

^aP < 0.01 vs non-diabetic control (db/+ mice, Mann-Whitney U-test).

^bP < 0.05 vs non-diabetic control (db/+ mice, Mann-Whitney U-test).

^cP < 0.01 vs non-diabetic control (db/+ mice, Mann-Whitney U-test).

^dP < 0.001 vs placebo (Mann-Whitney U-test). Data are presented as medians (min–max values). GBM: Glomerular basement membrane; FPs: Foot processes; EMPA: Empagliflozin.

Table 5 The relationships of glycemic control indicators, plasma creatinine and urinary albumin-to-creatinine ratio with renal structural parameters

Parameter	Fructosamine	Glycated albumin	Plasma creatinine	UACR
Mesangial volume, V_V	r = 0.69	r = 0.67	r = 0.57	r =0.81
Mesangial volume, V_V	P = 0.0002	P = 0.0004	P = 0.004	P = 0.000002
Capillary volume, V_V	r = 0.13	r = 0.11	r = 0.30	r = 0.05
Capillary volume, V_V	P > 0.05	P > 0.05	P > 0.05	P > 0.05
GBM width	r = 0.69	r = 0.69	r = 0.21	r = 0.53
GBM width	P = 0.0008	P = 0.007	P > 0.05	P = 0.02
Podocyte FPs, width	r = 0.62	r = 0.63	r = –0.15	r = 0.50
Podocyte FPs, width	P = 0.003	P = 0.003	P > 0.05	P = 0.03
Podocyte FPs, N_A	r = –0.57	r = -0.58	r = 0.04	r = –0.25
Podocyte FPs, N_A	P = 0.008	P = 0.007	P > 0.05	P > 0.05
Nephrin-positive areas in glomeruli, V_V	r = –0.68	r = –0.65	r = –0.51	r = –0.76
Nephrin-positive areas in glomeruli, V_V	P = 0.006	P = 0.009	P = 0.04	P = 0.001
TGF-β positive areas in glomeruli, V_V	r = 0.65	r = 0.65	r = 0.09	r = 0.67
TGF-β positive areas in glomeruli, V_V	P = 0.003	P = 0.002	P >0.05	P = 0.001

UACR: Urinary albumin-to-creatinine ratio; GBM: Glomerular basement membrane; FPs: Foot processes; Vv: Volumetric density; TGF-β: Transforming growth factor β. Spearman’s rank correlation coefficients are shown.

Citation: Klimontov VV, Korbut AI, Taskaeva IS, Bgatova NP, Dashkin MV, Orlov NB, Khotskina AS, Zavyalov EL, Klein T. Empagliflozin alleviates podocytopathy and enhances glomerular nephrin expression in db/db diabetic mice. World J Diabetes 2020; 11(12): 596-610
URL: https://www.wjgnet.com/1948-9358/full/v11/i12/596.htm
DOI: https://dx.doi.org/10.4239/wjd.v11.i12.596