title: Caspase-1, but Not Caspase-3, Promotes Diabetic Nephropathy.
abstract: Glomerular apoptosis may contribute to diabetic nephropathy (dNP), but the pathophysiologic relevance of this process remains obscure. Here, we administered two partially disjunct polycaspase inhibitors in 8-week-old diabetic (db/db) mice: M-920 (inhibiting caspase-1, -3, -4, -5, -6, -7, and -8) and CIX (inhibiting caspase-3, -6, -7, -8, and -10). Notably, despite reduction in glomerular cell death and caspase-3 activity by both inhibitors, only M-920 ameliorated dNP. Nephroprotection by M-920 was associated with reduced renal caspase-1 and inflammasome activity. Accordingly, analysis of gene expression data in the Nephromine database revealed persistently elevated glomerular expression of inflammasome markers (NLRP3, CASP1, PYCARD, IL-18, IL-1β), but not of apoptosis markers (CASP3, CASP7, PARP1), in patients with and murine models of dNP. In vitro, increased levels of markers of inflammasome activation (Nlrp3, caspase-1 cleavage) preceded those of markers of apoptosis activation (caspase-3 and -7, PARP1 cleavage) in glucose-stressed podocytes. Finally, caspase-3 deficiency did not protect mice from dNP, whereas both homozygous and hemizygous caspase-1 deficiency did. Hence, these results suggest caspase-3-dependent cell death has a negligible effect, whereas caspase-1-dependent inflammasome activation has a crucial function in the establishment of dNP. Furthermore, small molecules targeting caspase-1 or inflammasome activation may be a feasible therapeutic approach in dNP.
authors.affiliation: Department of Clinical Chemistry and Pathobiochemistry, Otto-von-Guericke-University, Magdeburg, Germany; Department of Molecular Genetics, University of Health Sciences, Khayaban-e-Jamia Punjab, Lahore, Pakistan;
authors.forename: Khurrum
authors.initials: K
authors.lastname: Shahzad
authors.affiliation: Department of Clinical Chemistry and Pathobiochemistry, Otto-von-Guericke-University, Magdeburg, Germany; Department of Internal Medicine I and Clinical Chemistry, German Diabetes Center (DZD), University of Heidelberg, Heidelberg, Germany.
authors.forename: Fabian
authors.initials: F
authors.lastname: Bock
authors.affiliation: Department of Clinical Chemistry and Pathobiochemistry, Otto-von-Guericke-University, Magdeburg, Germany;
authors.forename: Moh'd Mohanad
authors.initials: MM
authors.lastname: Al-Dabet
authors.affiliation: Department of Clinical Chemistry and Pathobiochemistry, Otto-von-Guericke-University, Magdeburg, Germany;
authors.forename: Ihsan
authors.initials: I
authors.lastname: Gadi
authors.affiliation: Department of Clinical Chemistry and Pathobiochemistry, Otto-von-Guericke-University, Magdeburg, Germany;
authors.forename: Shrey
authors.initials: S
authors.lastname: Kohli
authors.affiliation: Department of Clinical Chemistry and Pathobiochemistry, Otto-von-Guericke-University, Magdeburg, Germany;
authors.forename: Sumra
authors.initials: S
authors.lastname: Nazir
authors.affiliation: Department of Clinical Chemistry and Pathobiochemistry, Otto-von-Guericke-University, Magdeburg, Germany;
authors.forename: Sanchita
authors.initials: S
authors.lastname: Ghosh
authors.affiliation: Department of Clinical Chemistry and Pathobiochemistry, Otto-von-Guericke-University, Magdeburg, Germany;
authors.forename: Satish
authors.initials: S
authors.lastname: Ranjan
authors.affiliation: Department of Clinical Chemistry and Pathobiochemistry, Otto-von-Guericke-University, Magdeburg, Germany; Department of Cardiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; and.
authors.forename: Hongjie
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Clinical Chemistry and Pathobiochemistry, Otto-von-Guericke-University, Magdeburg, Germany;
authors.forename: Thati
authors.initials: T
authors.lastname: Madhusudhan
authors.affiliation: Department of Internal Medicine I and Clinical Chemistry, German Diabetes Center (DZD), University of Heidelberg, Heidelberg, Germany.
authors.forename: Peter P
authors.initials: PP
authors.lastname: Nawroth
authors.affiliation: Department of Clinical Chemistry and Pathobiochemistry, Otto-von-Guericke-University, Magdeburg, Germany; ikcp@med.ovgu.de berend.isermann@med.ovgu.de.
authors.forename: Berend
authors.initials: B
authors.lastname: Isermann
mesh_terms: D000818:Animals; D020170:Caspase 1 / Q000502:physiology*; D053148:Caspase 3 / Q000502:physiology*; D003928:Diabetic Nephropathies / Q000201:enzymology* / Q000209:etiology*; D058847:Inflammasomes; D051379:Mice
chemical_list: D058847:Inflammasomes; D053148:Caspase 3; D020170:Caspase 1
keywords: apoptosis; diabetic nephropathy; immunology; renal protection
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