Kidney Week

Abstract: SA-PO1010

Intra-Organ Cross-Talk via YB1 in the Kidney

Session Information

• CKD: Pathobiology - II
  November 05, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
  Abstract Time: 10:00 AM - 12:00 PM

Category: CKD (Non-Dialysis)

• 2203 CKD (Non-Dialysis): Mechanisms

Authors

• Isermann, Berend Heinrich, Institut für Laboratoriumsmedizin, Klinische Chemie und Molekulare Diagnostik, Universitätsklinikum Leipzig AöR, Leipzig, Saxony, Germany

Berend Heinrich Isermann,

• Manoharan, Jayakumar, Institut für Laboratoriumsmedizin, Klinische Chemie und Molekulare Diagnostik, Universitätsklinikum Leipzig AöR, Leipzig, Saxony, Germany

Jayakumar Manoharan,

• Elwakiel, Ahmed, Institut für Laboratoriumsmedizin, Klinische Chemie und Molekulare Diagnostik, Universitätsklinikum Leipzig AöR, Leipzig, Saxony, Germany

Ahmed Elwakiel,

• Zimmermann, Silke, Institut für Laboratoriumsmedizin, Klinische Chemie und Molekulare Diagnostik, Universitätsklinikum Leipzig AöR, Leipzig, Saxony, Germany

Silke Zimmermann,

• Lindquist, Jonathan A., Clinic of Nephrology and Hypertension, diabetes and Endocrinology, Magdeburg, Saxony-anhalt, Germany

Jonathan A. Lindquist,

• Gupta, Dheerendra, Institut für Laboratoriumsmedizin, Klinische Chemie und Molekulare Diagnostik, Universitätsklinikum Leipzig AöR, Leipzig, Saxony, Germany

Dheerendra Gupta,

• Kohli, Shrey, Institut für Laboratoriumsmedizin, Klinische Chemie und Molekulare Diagnostik, Universitätsklinikum Leipzig AöR, Leipzig, Saxony, Germany

Shrey Kohli,

• Shahzad, Khurrum, Institut für Laboratoriumsmedizin, Klinische Chemie und Molekulare Diagnostik, Universitätsklinikum Leipzig AöR, Leipzig, Saxony, Germany

Khurrum Shahzad,

• Brandt, Sabine, Clinic of Nephrology and Hypertension, diabetes and Endocrinology, Magdeburg, Saxony-anhalt, Germany

Sabine Brandt,

• Mertens, Peter R., Clinic of Nephrology and Hypertension, diabetes and Endocrinology, Magdeburg, Saxony-anhalt, Germany

Peter R. Mertens,

• Rana, Rajiv, Institut für Laboratoriumsmedizin, Klinische Chemie und Molekulare Diagnostik, Universitätsklinikum Leipzig AöR, Leipzig, Saxony, Germany

Rajiv Rana,

Background

Renal intra-organ glomerular-tubular crosstalk has been proposed, but the paracrine signals remain largely unknown. The ubiquitously expressed cold-shock protein YB1 regulates inflammation and renal diseases. Importantly, besides its intracellular functions, YB1 can be secreted upon acetylation, conveying extracellular effects. The role of podocyte YB1 remains unknown.

Methods

We analysed morphological and molecular changes in mice with podocyte-specific deletion of YB1 (YB1^ΔPod) and in mice expressing a nonsecretable YB1 mutant specifically in podocytes (YB1^K2A) to evaluate YB1’s role for glomerular-tubular cross-talk.

Results

Albuminuria was increased in unchallenged YB1^ΔPod mice compared to YB1^WT mice. Albuminuria in YB1^ΔPod mice was associated with increased tubular dilation and damage, but – surprisingly – reduced glomerular mesangial area expansion and podocyte foot process effacement. The increased tubular injury in YB1^ΔPod mice was associated with increased tubular TLR4 expression, NLRP3 inflammasome activation and increased renal inflammatory cell infiltrate. Mice expressing a nonsecretable YB-1 mutant (YB1^K2A) specifically in podocytes phenocopied the changes observed in YB1^ΔPod mice. In vitro, pre-treatment of TLR4 overexpressing tubular cells with recombinant YB1 inhibits NLRP3 inflammasome activation, suggesting that exogenous YB1 negatively modulates sterile inflammation in tubular cells via TLR4.

Conclusion

YB1 secreted from podocytes suppresses TLR-4- and NLRP3-mediated sterile inflammation in the tubular compartment, thus maintaining tubular physiology and kidney function. This uncovers a molecular mechanism of glomerular-tubular cross-talk required for normal renal physiology.

Funding

• Government Support – Non-U.S.