Metformin regulates inflammation and fibrosis in diabetic kidney disease through TNC/TLR4/NF-κB/miR-155-5p inflammatory loop

doi:10.4239/wjd.v12.i1.19

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Jan 15, 2021 (publication date) through Apr 19, 2024

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World Journal of Diabetes

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1948-9358

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Basic Study

World J Diabetes. Jan 15, 2021; 12(1): 19-46
Published online Jan 15, 2021. doi: 10.4239/wjd.v12.i1.19

Table 1 Sequences of siRNAs used for transfection

Gene	Sequence
TNC-siRNA	siRNA-TNC-T1 sense	5’-GCA UCU GUG AUG AUG ACU ATT-3’
	Anti-sense	5’-UAG UCA UCA UCA CAG AUG CTT-3’
	siRNA-TNC-T2 sense	5’-GCU GAG AAG GGC AGA CAU ATT-3’
	Anti-sense	5’-UAU GUC UGC CCU UCU CAG CTT-3’
	siRNA-TNC-T3 sense	5’-GCA UUU GUG AGG AUG GUU UTT-3’
	Anti-sense	5’-AAA CCA UCC UCA CAA AUG CTT-3’
	NC-siRNA-T	5’-UUC UCC GAA CGU GUC ACG UTT-3’
	Anti-sense	5’-ACG UGA CAC GUU CGG AGA ATT-3’
TLR4-siRNA	siRNA-TLR4	5’-CGA GCU GGU AAA GAA UUU ATT-3’
	Anti-sense	5’-UAA AUU CUU UAC CAG CUC GTT-3’
	NC-siRNA-TLR4 sense	5’-UUC UCC GAA CGU GUC ACG UTT-3’
	Anti-sense	5’-ACG UGA CAC GUU CGG AGA ATT-3’
miR-155-5p inhibitor	Inhibitor	5’-ACC CCU AUC ACA AUU AGC AUU AA-3’
	Inhibitor-NC	5’-CAG UAC UUU UGU GUA GUA CAA-3’

TNC: Tenascin-C; TLR4: Toll-like receptor-4; NC: Normal control.

Table 2 Comparison of clinical characteristics and biochemical data among groups [mean ± SEM, M (quartile)]

Group	n	Age (yr)	TG (mmol/L)	TC (mmol/L)	LDL-C (mmol/L)	HDL-C (mmol/L)	UA (μmol/L)	HbA1C (%)	TNC (pg/mL)	UACR (mg/g)	SBP (mmHg)	DBP (mmHg)	HOMA-IR
A	60	50 ± 1.29	1.17 (0.92-1.48)	4.58 ± 0.11	2.80 ± 0.11	1.44 ± 0.05	279.54 ± 8.43	5.40 (5.25-5.70)	15.20 (14.08-15.95)	9.92 (7.58-11.23)	119 ± 1.55	72 ± 1.29	1.02 ± 0.08
B	70	52 ± 1.79	0.91 (0.71-1.59)	5.13 ± 0.15	3.40 ± 0.14	1.29 ± 0.04	265.77 ± 7.08	7.30 (6.05-8.70)^a	15.07 (12.10-17.95)	16.76 (13.58-24.26)^a	118 ± 1.79	74 ± 0.84	2.53 ± 0.12^a
C	105	56 ± 1.07	2.07 (1.32-3.01)^a^,^b	4.62 ± 0.07	2.88 ± 0.06	1.12 ± 0.03^a	340.24 ± 8.17^a^,^b	8.40 (7.50-9.80)^a	17.07 (14.70-19.88)^a^,^b	44.85 (33.91-59.59)^a^,^b	126 ± 0.68	77 ± 0.68	4.68 ± 0.26^a^,^b
D	75	57 ± 1.5	1.84 (1.55-3.87)^a^,^b	4.49 ± 0.13	2.89 ± 0.11	1.00 ± 0.02^a^,^b	348.87 ± 10.83^a^,^b	7.30 (6.60-8.50)^a	18.96 (14.70-21.40)^a^,^b^,^c	56.17 (45.80-159.74)^a^,^b^,^c	152 ± 1.04^a^,^b^,^c	92 ± 1.5^a^,^b^,^c	4.85 ± 0.34^a^,^b
E	65	52 ± 0.99	2.08 (1.76-2.88)^a^,^b	5.61 ± 0.16^a^,^c^,^d	3.68 ± 0.13^a^,^c^,^d	1.21 ± 0.03	381.11 ± 10.47^a^,^b	7.80 (7.00-9.25)^a	18.71 (16.40-19.95)^a^,^b^,^c	871.58 (390.94-871.58)^a^,^b^,^c^,^d	127 ± 1.36	79 ± 0.99	5.65 ± 0.45^a^,^b
F	65	59 ± 1.36	1.99 (1.38-4.07)^a^,^b	4.84 ± 0.15	2.84 ± 0.12^e	1.11 ± 0.04^a	358.38 ± 8.27^a^,^b	9.10 (7.10-9.70)^a	21.16 (16.92-21.35)^a^,^b^,^c^,^d^,^e	1094.62 (790.00-5246.40)^a^,^b^,^c^,^d^,^e	160 ± 1.49^a^,^b^,^c^,^e	96 ± 1.86^a^,^b^,^c^,^e	5.75 ± 0.4^a^,^b

^aP < 0.05 compared with group A.

^bP < 0.05 compared with group B.

^cP < 0.05 compared with group C.

^dP < 0.05 compared with group D.

^eP < 0.05 compared with group E. 1 mmHg = 0.133 kPa; A: Healthy group; B: Normal albuminuria group; C: Microalbuminuria group; D: Microalbuminuria combined with hypertension group; E: Macroalbuminuria group; F: Macroalbuminuria combined with hypertension group. BMI: Body mass index; SBP: Systolic blood pressure; DBP: Diastolic blood pressure; UACR: Urinary albumin to creatinine ratio; HOMA-IR: Homeostasis model assessment-insulin resistance; HOMA-IR: Homeostasis model assessment of insulin resistance, = FRG × FINS / 22.5; HDL-C: High-density lipoprotein-cholesterol; LDL-C: Low-density lipoprotein-cholesterol; TC: Total cholesterol; TG: Triglycerides; UA: Uric acid; TNC: Tenascin-C.

Table 3 Correlation between tenascin-C levels and urinary albumin excretion rate

Index	lgTNC
Index	β	t	P value
Constant	0.0001	-31.965	0.001
lgHbA_1c	0.405	15.893	0.001
BMI	0.110	4.090	0.002
SBP	0.341	13.379	0.002
lgUACR	0.131	4.621	0.001

BMI: Body mass index; SBP: Systolic blood pressure; 1 mmHg = 0.133 kPa; UACR: Urinary albumin to creatinine ratio; TNC: Tenascin-C.

Table 4 Comparison of expression of tenascin-C, creatinine, and urea nitrogen in serum of rats [mean ± SD, M (quartile)]

Group	n	TNC (ng/mL)	Creatinine (mmol/L)	Urea nitrogen (mmol/L)
N	6	40.85 ± 2.99	37.27 ± 6.41	6.02 ± 1.57
D	6	59.25 ± 3.46^a	129.08 ± 39.88^a	22.48 ± 2.71

^aP < 0.05 compared with group. N, n = 6 for each group. N: Normal rat serum; D: Diabetic rat serum; TNC: Tenascin-C.

Table 5 Comparison of expression of tenascin-C in the supernatant of rat mesangial cell culture [mean ± SD, M (quartile)]

Group	n	TNC (ng/mL)
Ns	6	57.43 ± 5.94
Hs	6	70.13 ± 2.84^a

^aP < 0.05 compared with group Ns, n = 6 for each group. Ns: Normal condition supernatant (NG, 5.5 mmol/L glucose). Hs: High-glucose condition supernatant (HG, 30 mmol/L glucose).

Table 6 Real-time polymerase chain reaction primer sequences

Primer	Sequence
miR-155-5p	Forward	5’-GGT GCG GTT AAT GCT AAT TGT G-3’
	Reverse	5’-CAG AGC AGG GTC CGA GGTA-3’
U6	Forward	5’-CGC TTC GGC AGC ACA TAT AC-3’
	Reverse	5’-TTC ACG AAT TTG CGT GTC ATC-3’

Citation: Zhou Y, Ma XY, Han JY, Yang M, Lv C, Shao Y, Wang YL, Kang JY, Wang QY. Metformin regulates inflammation and fibrosis in diabetic kidney disease through TNC/TLR4/NF-κB/miR-155-5p inflammatory loop. World J Diabetes 2021; 12(1): 19-46
URL: https://www.wjgnet.com/1948-9358/full/v12/i1/19.htm
DOI: https://dx.doi.org/10.4239/wjd.v12.i1.19