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Kidney Week

Abstract: TH-OR059

Unanticipated Effect of C3a Receptor Antagonist in the Podocyte Injury of Diabetes

Session Information

Category: Diabetic Kidney Disease

  • 601 Diabetic Kidney Disease: Basic

Authors

  • Buelli, Simona, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy
  • Perico, Luca, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy
  • Corna, Daniela, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy
  • Locatelli, Monica, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy
  • Cassis, Paola, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy
  • Carminati, Claudia, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy
  • Zoja, Carlamaria, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy
  • Remuzzi, Giuseppe, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy
  • Benigni, Ariela, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy
  • Morigi, Marina, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy
Background

Podocyte damage is a crucial determinant for the development of diabetic nephropathy (DN) and is associated with mitochondrial dysregulation. Activation of the complement (C) system and C3a generation at glomerular level have been described in patients with DN. We previously demonstrated that C3a promoted podocyte dysfunction, although the intracellular mechanism is still ill-defined. Given the causal link between C activation and the derangement of mitochondrial homeostasis in different cellular systems, here we studied whether abnormal glomerular C activation could cause podocyte injury through its harmful effect on mitochondrial functions in DN.

Methods

Changes in podocyte phenotype and mitochondrial structural and functional integrity were investigated in BTBR ob/ob mice treated with vehicle or C3a receptor (C3aR) antagonist SB290157 between 9 and 14 weeks of age, and in cultured podocytes treated with C3a (1μM, 6h).

Results

BTBR ob/ob mice exhibited increased albuminuria over time, podocyte loss and glomerular damage accompanied by increased C3 and C3a staining and C3aR overexpression. Decreased glomerular nephrin and a-actinin4 levels, coupled with induction of integrin-linked kinase, were observed. Treating DN mice with C3aR antagonist enhanced podocyte density and preserved their phenotype, thus limiting albuminuria (SB290157: 120±21 vs vehicle: 303±49 μg/day, p<0.01) and glomerular injury. Ultrastructural and functional mitochondrial changes in podocytes were associated with increased protein oxidation, and were normalized by SB290157. In cultured podocytes exposed to C3a, mitochondrial fragmentation and altered membrane permeability, associated with downregulation of the antioxidant SOD2, proved that C3a induced mitochondrial dysfunction directly. C3a also altered podocyte energy production without affecting the glycolytic pathway. Notably, C3a-induced podocyte motility was inhibited by SS-31, a peptide with mitochondrial protective effects, suggesting that disturbances in mitochondrial function in response to C3a affect podocyte adhesive properties.

Conclusion

These data indicate that C3a blockade is a novel therapeutic strategy in DN for preserving podocyte integrity through the maintenance of mitochondrial functions.

Funding

  • Private Foundation Support