Genetic Deletion of Cell Division Autoantigen 1 Retards Diabetes-Associated Renal Injury

Abstract

Cell division autoantigen 1 (CDA1) enhances TGF-b signaling in renal and vascular cells, and renal expression of CDA1 is elevated in animal models of diabetes. In this study, we investigated the genetic deletion of Tspyl2, the gene encoding CDA1, in C57BL6 and ApoE knockout mice. The increased renal expression of TGF-b1, TGF-b type I and II receptors, and phosphorylated Smad3 associated with diabetes in wild-type mice was attenuated in diabetic CDA1 knockout mice. Notably, CDA1 deletion significantly reduced diabetes-associated renal matrix accumulation and immunohistochemical staining for collagens III and IV and attenuated glomerular and tubulointerstitial injury indices, despite the presence of persistent hyperglycemia, polyuria, renal hypertrophy, and hyperfiltration. Furthermore, CDA1 deletion reduced gene expression of TGF-b1 receptors in the kidney, resulting in a functionally attenuated response to exogenous TGF-b, including reduced levels of phosphorylated Smad3 and ERK1/2, in primary kidney cells from CDA1 knockout animals. Taken together, these data suggest that CDA1 deletion reduces but does not block renal TGF-b signaling. Because direct antagonism of TGF-b or its receptors has unwanted effects, CDA1 may be a potential therapeutic target for retarding DN and perhaps, other kidney diseases associated with TGF-b-mediated fibrogenesis.

Genetic Targeting or Pharmacologic Inhibition of NADPH Oxidase Nox4 Provides Renoprotection in Long-Term Diabetic Nephropathy

“…We used ApoE 2/2 mice because streptozotocin-induced diabetes in ApoE 2/2 mice is a well characterized model of advanced renal injury with prominent ECM accumulation. 28,29 Importantly, we translated these findings into a potential clinical therapy by showing that Nox inhibition in diabetic ApoE 2/2 mice using a pharmacologic strategy resulted in a similar degree of renoprotection to that observed with deletion of Nox4.…”

Novel targets of antifibrotic and anti-inflammatory treatment in CKD

“…55 Interestingly, targeted deletion of Tspyl2 did not affect other features, such as hyperglycaemia, renal hypertrophy, or hyperfiltration, in these diabetic mice. 55 Although additional studies are required to evaluate the potential effect of CDA1 inhibition on sustained protein-uria and progressive fibrosis, its actions in reducing TGF-β-mediated matrix accumulation provide support for CDA1 as a potential therapeutic target to slow the progression of CKD.…”

“…In a separate study, the role of TSPY-like protein 2 in regulating TGF-β signalling was demonstrated. 55 In diabetic Tspyl2 –/– mice there was reduced renal accumulation of extra cellular matrix proteins and decreased glomerular and tubulointerstitial injury were observed, along with decreased gene expression of TGF-β and TGF-β type I receptor, and decreased levels of phosphorylated Smad3. 55 Interestingly, targeted deletion of Tspyl2 did not affect other features, such as hyperglycaemia, renal hypertrophy, or hyperfiltration, in these diabetic mice.…”

“…55 In diabetic Tspyl2 –/– mice there was reduced renal accumulation of extra cellular matrix proteins and decreased glomerular and tubulointerstitial injury were observed, along with decreased gene expression of TGF-β and TGF-β type I receptor, and decreased levels of phosphorylated Smad3. 55 Interestingly, targeted deletion of Tspyl2 did not affect other features, such as hyperglycaemia, renal hypertrophy, or hyperfiltration, in these diabetic mice. 55 Although additional studies are required to evaluate the potential effect of CDA1 inhibition on sustained protein-uria and progressive fibrosis, its actions in reducing TGF-β-mediated matrix accumulation provide support for CDA1 as a potential therapeutic target to slow the progression of CKD.…”

“…54,55 CDA1 was first considered for its antiproliferative effects; 56 however, the critical role of CDA1 in TGF-β signalling was demonstrated in models of diabetic nephropathy. CDA1 was upregulated in tubular cells and podocytes in rodent and human diabetic kidneys.…”