Kidney Week

Abstract: SA-PO255

SGLT2 Inhibitors Attenuate Protein Abundance of Collectin Kidney 1 and Mannose-Binding Lectin in the Kidney and Liver in Mice with Experimental Diabetes

Session Information

• Diabetic Kidney Disease: Basic - 2
  October 26, 2024 | Location: Exhibit Hall, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Diabetic Kidney Disease

• 701 Diabetic Kidney Disease: Basic

Authors

• Jensen, Mia, Unit for Cardiovascular and Renal research, Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark

Mia Jensen, PhD

• Enggaard, Camilla, Unit for Cardiovascular and Renal research, Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark

Camilla Enggaard

• Thiel, Steffen, Department of Biomedicine, Aarhus University, Aarhus, Denmark

Steffen Thiel, PhD

• Palarasah, Yaseelan, Unit for Cancer and Inflammation Research, Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark

Yaseelan Palarasah, PhD

• Svenningsen, Per, Unit for Cardiovascular and Renal research, Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark

Per Svenningsen, PhD

• Jensen, Boye, Unit for Cardiovascular and Renal research, Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark

Boye Jensen, MD, PhD

Background

Diabetic nephropathy (DN) is a leading cause of end-stage renal disease. Sodium-glucose cotransport-2 (SGLT-2) inhibitors have significantly improved the treatment of DN and its cardiovascular complications. The mechanism behind the broad protection is elusive. We hypothesized that the lectin pathway of the complement system contributes to early kidney injury in DN. Here we investigate if 1) experimental diabetes in mice is associated selectively with increased collectin kidney 1 (CL-K1) abundance and binding, 2) if SGLT-2 inhibitors attenuate CL-K1 and complement activation, and 3) if a functional deletion of CL-K1 protects against diabetic kidney injury.

Methods

Streptozotocin (STZ) and vehicle were intraperitoneally injected in male wild-type (WT) FVB or CL-K1 knockout (KO) mice for 5 consecutive days to induce diabetes. Experiment 1: WT STZ(n=10) and WT vehicle (VEH)-treated(n=10) mice were sacrificed on day 14 and day 35. Experiment 2: WT STZ mice were orally treated with Dapagliflozin(n=10) or vehicle(n=10) for 10 days. Experiment 3: WT STZ(n=4), WT VEH(n=4), CL-K1 KO STZ(n=4), and CL-K1 KO VEH(n=4). Urine, plasma, and organs were collected. mRNA expression and protein abundance of complement products were determined by western blotting, qPCR, and RNAscope.

Results

STZ-treated mice exhibited increased plasma glucose, kidney weight, blood urea nitrogen, urinary excretion of albumin, and KIM-1. CL-K1 protein level increased significantly and progressively in kidney tissue and plasma but not in liver tissue in STZ-treated mice. MBL-C and MASP-1 increased in plasma following STZ. CL-K1 and MBL-C mRNA abundances increased in the kidney. Dapagliflozin lowered fasting plasma glucose (29.7 [5.50] vs. 33.3 [2.10] mmol/L,p<0.01) and protein abundance of CL-K1 in liver (0.38 ± 0.13 vs.1.0 ± 0.46 CL-K1/Beta-actin,p<0.05) and kidney (0.29 ± 0.34 vs.1.0 ± 0.52 CL-K1/Beta-actin,p<0.05), while corresponding mRNA levels were unchanged. CL-K1 KO did not affect kidney injury markers, but a trend toward lower levels of urinary excretion of albumin and KIM-1 was seen in STZ-treated CL-K1 KO mice compared to STZ WT.

Conclusion

CL-K1 increases in kidney and plasma with the progression of kidney injury, and SGLT-2 inhibitors may lower complement activation in diabetic kidneys.

Funding

• Private Foundation Support