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Abstract: TH-PO875

The Leptin Receptor in Mouse Kidney: Gene Expression of Splice Variants and a Potential Anti-Albuminuric Role in Podocytes

Session Information

Category: Diabetic Kidney Disease

  • 601 Diabetic Kidney Disease: Basic

Authors

  • Fattah, Hadi, Department of Medicine, University of California, San Diego & VA San Diego Healthcare System, San Diego, California, United States
  • Huang, Winnie, Department of Medicine, University of California, San Diego & VA San Diego Healthcare System, San Diego, California, United States
  • Patel, Rohit, Department of Medicine, University of California, San Diego & VA San Diego Healthcare System, San Diego, California, United States
  • Fu, Yiling, Department of Medicine, University of California, San Diego & VA San Diego Healthcare System, San Diego, California, United States
  • Nespoux, Josselin, Department of Medicine, University of California, San Diego & VA San Diego Healthcare System, San Diego, California, United States
  • Freeman, Brent, Department of Medicine, University of California, San Diego & VA San Diego Healthcare System, San Diego, California, United States
  • Vallon, Volker, Department of Medicine, University of California, San Diego & VA San Diego Healthcare System, San Diego, California, United States
Background

Leptin regulates food intake and metabolism primarily through leptin receptor splice variant B (LEPRB) in brain and liver. Little is known about LEPR splice variants in the kidney or their function.

Methods

A) Urinary albumin to creatinine ratios (UACR) and mRNA expression of renal LEPR splice variants LEPRA, LEPRB & LEPRC (by RT-qPCR, norm. to b-actin) were determined in non-diabetic mice (nd) and in obese/hyperglycemic mice lacking endogenous leptin (ob/ob) ± leptin substitution for 6 days (osmotic minipump: 4.7 µg/day s.c.)(all mice ~4 months of age & BTBR background)(n=5-8/group). B) C57BL6 mice with knockdown of LEPRs in podocytes (podocin-Cre) were generated to determine GFR (by plasma elimination kinetics of FITC-sinistrin in conscious mice) and UACR (n=8/group).

Results

A) Leptin substitution restored plasma leptin levels in ob/ob (4.3±0.3 vs 4.6±0.7 ng/ml in nd mice) and reduced hyperglycemia (275±29 vs 573±17 mg/dl in vehicle-treated ob/ob; P<0.05). In all 3 groups, the renal mRNA expression was higher for LEPRA vs LEPRB or LEPRC, and the expression of all 3 variants was higher in medulla vs cortex. The cortical expression of all 3 variants was lower in ob/ob vs nd, and not significantly affected by leptin substitution. Medullary expression was more variable. The transcription factor Atf3 is a newly discovered mediator of brain LEPRB. Atf3 mRNA was increased in kidney cortex & medulla in ob/ob vs nd and not altered by leptin substitution. The latter, however, reduced UACR in ob/ob (pre to post: 650±145 to 167±45 µg/mg; P<0.05) whereas vehicle was ineffective (632±283 to 819±217 µg/mg). B) Ten week old male mice with LEPR knockdown in podocytes had similar blood glucose (129±5 vs 117±3 mg/dl) and GFR (436±16 vs 443±18 µl/min) but enhanced UACR vs wild-type littermates (20.5±7.4 vs 8.8±1.5 µg/mg; P<0.05).

Conclusion

On mRNA level, LEPRA is the dominant renal splice variant of the LEPR, and LEPR splice variants are higher expressed in medulla vs cortex. Absence of leptin did not upregulate mRNA expression of LEPR splice variants in cortex or medulla, but enhanced mRNA of the LEPRB target gene Atf3. Functional studies were consistent with an anti-albuminuric effect of leptin, potentially via LEPR in podocytes.

Funding

  • Other NIH Support