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.2024 Oct 18;10(20):e39552.
doi: 10.1016/j.heliyon.2024.e39552. eCollection 2024 Oct 30.

Morphometric analysis of the intergenerational effects of protein restriction on nephron endowment in mice

Affiliations

Morphometric analysis of the intergenerational effects of protein restriction on nephron endowment in mice

Fabiola Diniz et al. Heliyon..

Abstract

Background: Parental nutritional status is crucial in shaping offspring's kidney development. However, the association between a protein-restrictive diet and its intergenerational impact on kidney development remains unclear.

Methods: We conducted multigenerational morphometric measurements to investigate the effects of parental protein deprivation on offspring kidney development across four generations. F0 mice were divided into two groups and fed a normal protein diet (NPD) or a low-protein diet (LPD) for three weeks before mating and continued these diets throughout gestation and lactation. Body weight (BW), kidney weight (KW), KW/BW ratio, nephron counts, and blood pressure were assessed in F1 pups. To examine paternal effects, we bred CD1 females on an NPD with males on an LPD. BW, KW, KW/BW, and nephron counts were measured at P20. To measure the transgenerational effect of parental LPD on kidney development, F1 offspring (from parents on LPD) were fed NPD upon weaning. These F1 offspring were bred at 6 weeks of age to produce F2, F3 and F4 generations. Kidney metrics were evaluated across generations.

Results: The average body weight of P0 pups from parents on NPD was 1.61g, while pups from parental LPD weighed an average of 0.869g, a decrease of 54 % (p = 6.9e-11, Wilcoxon test). F1 from parental LPD have significantly smaller kidneys than the control, with an average combined kidney weight of 0.0082g versus 0.0129g, a 37 % decrease (p = 3.2e-02, Wilcoxon test). P20 BW and KW remained low in LPD offspring. These effects persisted for 4 generations (F1 to F4) with an average glomerular count reduction of roughly 20 %. F3 and F4 showed wider variability in glomerular counts but were not statistically significant compared to controls.

Conclusions: Both maternal and paternal LPD significantly affected offspring nephron endowment. Our study underscores the complex nature of nutritional transgenerational effects on kidney development, emphasizing the importance of both maternal and paternal dietary impacts on kidney development and the developmental origin of adult disease.

Keywords: Developmental programming; Hypertension; Kidney; Low protein diet; Nephron endowment; Oligonephropathy.

© 2024 The Authors.

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Conflict of interest statement

The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Samir El-Dahr reports financial support was provided by 10.13039/100000002National Institutes of Health. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Figures

Fig. 1
Fig. 1
Study design. Twenty-one-day-old CD1 mice (both males and females) were assigned to either a Normal Protein Diet (NPD) or a Low Protein Diet (LPD) for three weeks. After this period, these mice were bred to produce the F1 generation. The breeding scheme comprised three original groups: 1) male and female on NPD; 2) males on LPD and females fed an NPD and 3) males and females on LPD. These NPD and LPD offspring were either collected for analysis at different time points (P0 and P20) or placed on NPD at weaning (P20) and bred to generate an F2 generation. This procedure was repeated to produce an F3 and F4 generation. The collected tissues were analyzed as described in the methods section. Parental generation and start point (F0); F1 – F4 subsequent generations. Notice that only the F0 generation was put on an NPD or LPD, all subsequent generations were fed an NPD.
Fig. 2
Fig. 2
LPD impact on mouse and kidney development. P0 LPD offspring are born with lower body weight than control (BW mean ± sd NPD F1 = 1.61 ± 0.15g, n = 42; LPD F1 = 0.87 ± 0.17g, n = 22, p = 6.9e-11, Wilcoxon test) (A). LPD offspring mice have decreased kidney weight (KW mean ± sd NPD F1 = 0.013 ± 0.002g; LPD F1 = 0.008 ± 0.002g, p = 3.2e-8, Wilcoxon test) (B). The KW/BW ratio was increased in the LPD offspring KW/BW mean ± sd NPD F1 = 0.008 ± 0.001g; LPD F1 = 0.009 ± 0.001g, p = 0.004) (C). Morphological analysis of P20 F1 offspring shows the impact of LPD on normal development (D–F). P20 Body weight (NPD F1 = 16.3 ± 1.57g, n = 18; LPD F1 14.0 ± 1.57g, n = 17, p = 9e-4, Wilcoxon test) and kidney weight (NPD 0.232 ± 0.0369g; LPD 0.179 ± 0.0297g, p = 0.00012, Wilcoxon test) were significantly reduced in LPD offspring (G, H). The KW/BW ratio was decreased in the P20 LPD offspring (KW/BW NPD F1 = 0.0138 ± 0.00180g, 18; LPD F1 = 0.0127 ± 0.00133g, n = 17, p = 0.0048, Wilcoxon test) (I). LPD impacted body weight and kidney weight in both males and females to a similar extent (J and K). The glomerular counts at P20 were reduced in the F1 generation from F0 fed an LPD diet (NPD F1 = 158 ± 18, 37; LPD = 129 ± 21, 27, p = 0.00025, Wilcoxon test) (L). H&E staining of tissue sections from the P20 kidney of parental NPD and LPD groups, the round structures indicated with black arrows are glomeruli (M and N). Values are presented as mean ± sd. Scale bar 200 μm.
Fig. 3
Fig. 3
LPD impact on mouse and kidney development persists in adult animals. Body weight is not different in LPD vs NPD offspring at 3 months (BW mean ± sd NPD = 45.4 ± 6.67g; LPD = 43.3 ± 6.35g) (A). Body weight differences were normalized in adult males and females (B). The kidney weight remained reduced in adult animals (KW mean ± sd NPD = 0.661 ± 0.185g; LPD = 0.473 ± 0.104g) (C). The KW reduction was observed in both males and females (D). The KW/BW ratio remained decreased in the adult LPD offspring (KW/BW mean ± sd NPD = 0.0144 ± 0.00265; LPD = 0.0110 ± 0.00218g) (E). The reduction in the KW/BW was noticeable in both sexes, but statistical significance was only reached in males (F). There was no difference in systolic blood pressure measurements of F1 offspring from F0 parents fed an LPD or NPD at 3 months of age (NPD BP = 125 ± 10.3 mmHg; LPD BP = 126 ± 9.71 mmHg) (G, H). Sample size and p-value are reported in the figure. Values are presented as mean ± sd.
Fig. 4
Fig. 4
Paternal contribution to LPD impact on mouse and kidney development. Morphological analysis of P20 F1 offspring shows the impact of paternal LPD on normal kidney development. Paternal LPD leads to a reduction in body weight at P20 F1 offspring (F1 control BW = 16.3 ± 1.57g, n = 18; paternal LPD 12.2 ± 1.83g, n = 27, p = 5.7e-7, Wilcoxon test) in both sexes (A and B) and kidney weight (F1 control KW = 0.232 ± 0.0369g; paternal LPD 0.165 ± 0.0319g, p = 1.8e-6, Wilcoxon test) (C and D). KW/BW ratio was decreased (KW/BW F1 control = 0.0142 ± 0.00168g; paternal LPD = 0.0134 ± 0.00156g, p = 1.8e-6) (E). The glomerular counts at P20 were reduced in the F1 generation from the paternal-fed LPD (F1 = 158 ± 18; paternal LPD = 144 ± 11.6, n = 18, p = 0.002) (F). H&E staining of tissue sections from P20 kidney of paternal NPD and LPD groups. the round structures indicated with black arrows are glomeruli (G and H). Values are presented as mean ± sd. Scale bar 200 μm.
Fig. 5
Fig. 5
Transgenerational impact of LPD on F2 kidney development. P20 F2 offspring from F0 fed with an LPD shows reduced Body weight (NPD-F1 BW = 16.3 ± 1.57g, n = 18; F2 = 12.1 ± 1.85g, n = 31, p = 4.2e-8, Wilcoxon test) in both sexes (A and B). Kidney weight (KW F1 = 0.218 ± 0.0431g; F2 KW = 0.186 ± 0.116g, p = 0.0003, Wilcoxon test) was significantly reduced in LPD offspring in both sexes (C, D). The KW/BW ratio was decreased in the P20 LPD offspring (KW/BW F1 control = 0.0142 ± 0.00168g; F2 = 0.0153 ± 0.00905g, p = 0.7, Wilcoxon test) (E). The glomerular counts at P20 were reduced in the F1 generation from F0 fed an LPD (F1 = 158 ± 18, n = 37; F2 = 147 ± 9.8, n = 14, p = 0.033, Wilcoxon test) (F). H&E staining of tissue sections from P20 kidney of parental NPD and F2 from F0-fed LPD groups, the round structures indicated with black arrows are glomeruli (G and H). Values are presented as mean ± sd. Scale bar 200 μm.
Fig. 6
Fig. 6
Transgenerational impact of LPD on F3 kidney development. P20 F3 offspring from F0 fed with an LPD shows reduced Body weight (F1 BW = 15.6 ± 1.90g, n = 18; F3 = 11.8 ± 2.32g, n = 23, p = 1.2e-5, Wilcoxon test) in both sexes (A and B). Kidney weight (F1 KW = 0.218 ± 0.0431g; F3 KW = 0.169 ± 0.0172g, p = 0.00058) was significantly reduced in LPD offspring in both sexes (C, D). The KW/BW ratio was decreased in the P20 LPD offspring (KW/BW F1 control = 0.0142 ± 0.00168g; F3 = 0.0148 ± 0.00259g, p = 0.38, Wilcoxon test) (E). The glomerular counts at P20 were reduced in the F1 generation from F0 fed an LPD (F1 = 159 ± 18, n = 37; F3 = 148 ± 15.3, n = 19, p = 0.079, Wilcoxon test) (F). H&E staining of tissue sections from P20 kidney of parental NPD and F2 from F0-fed LPD groups, the round structures indicated with black arrows are glomeruli (G and H). Values are presented as mean ± sd. Scale bar 200 μm.
Fig. 7
Fig. 7
Transgenerational impact of LPD on F4 kidney development. P20 F4 offspring from F0 fed with an LPD shows reduced Body weight (F1 BW = 15.6 ± 1.90g, n = 18; F4 = 11.9 ± 2.58g, n = 25, p = 1.6e-5, Wilcoxon test in both sexes (A and B). Kidney weight (F1 KW = 0.218 ± 0.0431g; F4 KW = 0.180 ± 0.0311g, p = 0.002) was significantly reduced in LPD offspring in both sexes (C, D). The KW/BW ratio was decreased in the P20 LPD offspring (KW/BW F1 = 0.0138 ± 0.00180g; F4 = 0.0152 ± 0.00156g, p = 0.12, Wilcoxon test) (E). The glomerular counts at P20 were reduced in the F1 generation from F0 fed an LPD (F1 = 158 ± 18, n = 37; F4 = 148 ± 8.83, n = 13, p = 0.076, Wilcoxon test) (F). H&E staining of tissue sections from P20 kidney of parental NPD and F2 from F0-fed LPD groups, the round structures indicated with black arrows are glomeruli (G and H). Values are presented as mean ± sd. Scale bar 200 μm.
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