Poly(ADP-ribose) polymerase-1 (PARP-1) gene deficiency alleviates diabetic kidney disease - PubMed (original) (raw)

Poly(ADP-ribose) polymerase-1 (PARP-1) gene deficiency alleviates diabetic kidney disease

Hanna Shevalye et al. Biochim Biophys Acta. 2010 Nov.

Abstract

Poly(ADP-ribose)polymerase (PARP) inhibitors prevent or alleviate diabetic nephropathy. This study evaluated the role for PARP-1 in diabetic kidney disease using the PARP-1-deficient mouse. PARP-1-/- and the wild-type (129S1/SvImJ) mice were made diabetic with streptozotocin, and were maintained for 12 weeks. Final blood glucose concentrations were increased ∼ 3.7-fold in both diabetic groups. PARP-1 protein expression (Western blot analysis) in the renal cortex was similar in non-diabetic and diabetic wild-type mice (100% and 107%) whereas all knockouts were PARP-1-negative. PARP-1 gene deficiency reduced urinary albumin (ELISA) and protein excretion prevented diabetes-induced kidney hypertrophy, and decreased mesangial expansion and collagen deposition (both assessed by histochemistry) as well as fibronectin expression. Renal podocyte loss (immunohistochemistry) and nitrotyrosine and transforming growth factor-β₁ accumulations (both by ELISA) were slightly lower in diabetic PARP-1-/- mice, but the differences with diabetic wild-type group did not achieve statistical significance. In conclusion, PARP-1-/- gene deficiency alleviates although does not completely prevent diabetic kidney disease.

Copyright © 2010 Elsevier B.V. All rights reserved.

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Figures

Fig. 1

Fig. 1

A) Representative Western blot analysis of renal cortex poly(ADP-ribose) polymerase-1 and B) poly(ADP-ribose)polymerase-1 content (densitometry), in control and diabetic wild-type and poly(ADP-ribose) polymerase-1-deficient mice. C – control; D – diabetic, PARP-1 – poly(ADP-ribose) polymerase-1. Mean ± SEM, n = 8–10 per group.

Fig. 2

Fig. 2

A) Representative Western blot analysis of renal cortex poly(ADP-ribosyl)ated proteins and B) poly(ADP-ribosyl)ated protein content (densitometry), in control and diabetic wild-type and poly(ADP-ribose)polymerase-1-deficient mice. C – control; D – diabetic, PARP-1 – poly(ADP-ribose) polymerase-1. Mean ± SEM, n = 9–12 per group. *, ** - p < 0.05 and < 0.01 vs corresponding non-diabetic groups.

Fig. 3

Fig. 3

A) Kidney weights and B) kidney weight-to-body weight ratios, in control and diabetic wild-type and poly(ADP-ribose)polymerase-1-deficient mice. C – control; D – diabetic, PARP-1 – poly(ADP-ribose) polymerase-1. Mean ± SEM, n = 10–15 per group. ** - p < 0.01 vs corresponding non-diabetic groups; ## - p < 0.01 vs diabetic wild-type mice.

Fig. 4

Fig. 4

A) Representative microphotographs and B) color intensities of PAS-positive substance stainings in the renal cortex in control and diabetic wild-type and poly(ADP-ribose)polymerase-1-deficient mice. C – control; D – diabetic, PARP-1 – poly(ADP-ribose) polymerase-1. Magnification x 400. Mean ± SEM, n = 10 per group. ** - p < 0.01 vs corresponding non-diabetic groups; # - p < 0.05 vs diabetic wild-type mice.

Fig. 5

Fig. 5

A) Representative Western blot analysis of renal cortex fibronectin and B) fibronectin content (densitometry), in control and diabetic wild-type and poly(ADP-ribose)polymerase-1-deficient mice. C – control; D – diabetic, PARP-1 – poly(ADP-ribose) polymerase-1. Mean ± SEM, n = 10–13 per group. *, ** - p < 0.05 and < 0.01 vs corresponding non-diabetic groups; ## - p < 0.01 vs diabetic wild-type mice.

Fig. 6

Fig. 6

A) Representative microphotographs of glomerular podocyte immunostaining and B) podocyte counts, in control and diabetic wild-type and poly(ADP-ribose)polymerase-1-deficient mice. C – control; D – diabetic, PARP-1 – poly(ADP-ribose) polymerase-1. Magnification x 400. Mean ± SEM, n = 10 per group. ** - p < 0.01 vs corresponding non-diabetic groups.

Fig. 7

Fig. 7

A) Transforming growth factor-β and B) nitrotyrosine concentrations, in the renal cortex in control and diabetic wild-type and poly(ADP-ribose)polymerase-1-deficient mice. C – control; D – diabetic, PARP-1 – poly(ADP-ribose) polymerase-1. Mean ± SEM, n = 9–14 per group. ** - p < 0.01 vs corresponding non-diabetic groups.

Fig. 8

Fig. 8

A) Representative microphotographs and B) percentage of positively stained for collagen area in the renal cortex in control and diabetic wild-type and poly(ADP-ribose)polymerase-1-deficient mice. C – control; D – diabetic, PARP-1 – poly(ADP-ribose) polymerase-1. Magnification x 200. Mean ± SEM, n = 8–10 per group. ** - p < 0.01 vs corresponding non-diabetic groups; ## - p < 0.01 vs diabetic wild-type mice.

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