Abstract: FR-PO1003
Protective Effects of Lrp2 Knockout Are Independent of Sex-Specific Renal Injury in Mice on Western Diet
Session Information
- CKD Mechanisms: From Mendel to Mars
November 03, 2023 | Location: Exhibit Hall, Pennsylvania Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: CKD (Non-Dialysis)
- 2303 CKD (Non-Dialysis): Mechanisms
Authors
- Youm, Elynna B., University of Pittsburgh, Pittsburgh, Pennsylvania, United States
- Albalawy, Wafaa N., University of Pittsburgh, Pittsburgh, Pennsylvania, United States
- Marciszyn, Allison L., University of Pittsburgh, Pittsburgh, Pennsylvania, United States
- Lashway, Jared, University of Pittsburgh, Pittsburgh, Pennsylvania, United States
- Bondi, Corry D., University of Pittsburgh, Pittsburgh, Pennsylvania, United States
- Boyd-Shiwarski, Cary R., University of Pittsburgh, Pittsburgh, Pennsylvania, United States
- Tan, Roderick J., University of Pittsburgh, Pittsburgh, Pennsylvania, United States
- Jurczak, Michael J., University of Pittsburgh, Pittsburgh, Pennsylvania, United States
- Weisz, Ora A., University of Pittsburgh, Pittsburgh, Pennsylvania, United States
Background
Megalin (Lrp2) is a multiligand receptor that plays a crucial role in maintaining endocytic flux in the kidney proximal tubule (PT). Knockout (KO) or disabled function of megalin is protective against nephrotoxicity, though the mechanism(s) are unknown. We previously found that KO of Lrp2 in opossum kidney cells and mice reduces transcription of sodium-glucose cotransporter-2 (Sglt2). Because Sglt2 inhibition attenuates hyperglycemia in diabetic patients and protects against kidney disease in non-diabetic patients, we compared metabolic and renal function in male and female wild type (WT) and Lrp2 KO mice fed regular chow (RC) or Western diets (WD).
Methods
Sixteen-week-old WT or Lrp2 KO mice on RC were administered glucose tolerance tests (GTT) and then placed in metabolic cages for 48 h. The mice were tested again after 6 weeks on WD. Spot urine samples were also collected. Urine, tissue, and blood samples were collected at sacrifice for analysis.
Results
Male and female Lrp2 KO mice on RC and WD had increased glucose tolerance compared to WT mice. Lrp2 KO mice also consumed more water and had increased activity. Respiratory exchange ratio (RER) data suggests a difference in fatty acid oxidation between genotypes. These features persist in male and female Lrp2 KO mice fed WD, and both gained far less fat mass than their WT counterparts. Strikingly, whereas female Lrp2 KO mice had normal blood electrolyte, BUN, and creatinine levels, these values suggested kidney injury in male Lrp2 KO mice on WD. Histology and qPCR analyses confirmed that Lrp2 KO male mice exhibited significant kidney injury.
Conclusion
Lrp2 KO mice had increased glucose tolerance, water consumption, and RER compared to WT mice. This phenotype is similar to those of Sglt2 KO mice or WT mice treated with Sglt2 inhibitors. Remarkably, these features persist following WD in both female and male Lrp2 KO mice, despite male mice exhibiting significant kidney disease. These results suggest that the protective effects of Lrp2 KO are independent of kidney injury. Further studies are underway to understand how megalin regulates PT function in a high-fat environment.
Funding
- NIDDK Support