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Reno-protective effect of protocatechuic acid is independent of sex-related differences in murine model of UUO-induced kidney injury

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Abstract

Background

Obstructive nephropathy is a condition often caused by urinary tract obstruction either anatomical (e.g., tumors), mechanical (e.g., urolithiasis), or compression (e.g., pregnancy) and can progress to chronic kidney disease (CKD). Studies have shown sexual dimorphism in CKD, where males were found to have a more rapid decline in kidney function following kidney injury compared to age-matched females. Protocatechuic acid (PCA), an anti-oxidant and anti-inflammatory polyphenolic compound, has demonstrated promising effects in mitigating drug-induced kidney injuries. The current study aims to explore sexual dimorphism in kidney injury after unilateral ureteral obstruction (UUO) and assess whether PCA treatment can mitigate kidney injury in both sexes.

Methods

UUO was induced in 10–12 weeks old male and female C57BL/6J mice. Mice were categorized into four groups (n = 6–8/group); Sham, Sham plus PCA (100 mg/kg, I.P daily), UUO, and UUO plus PCA.

Results

After 2 weeks of induction of UUO, markers of kidney oxidative stress (TBARs), inflammation (IL-1α and IL-6), tubular injury (neutrophil gelatinase-associated lipocalin, NGAL and urinary kidney injury molecule-1, KIM-1), fibrosis (Masson's trichrome staining, collagen IV expression, MMP-2 and MMP-9) and apoptosis (TUNEL+ cells, active caspase-1 and caspase-3) were significantly elevated in both males and females relative to their sham counterparts. Males exhibited significantly greater kidney oxidative stress, inflammation, fibrosis, and apoptosis after induction of UUO when compared to females. PCA treatment significantly attenuated UUO-induced kidney injury, inflammation, fibrosis, and apoptosis in both sexes.

Conclusion

Our findings suggest a differential gender response to UUO-induced kidney injury with males being more sensitive to UUO-induced kidney inflammation, fibrosis, and apoptosis than age-matched females. Importantly, PCA treatment reduced UUO-induced kidney injury in a sex-independent manner which might be attributed to its anti-oxidant, anti-inflammatory, anti-fibrotic, and anti-apoptotic properties.

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Data availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author upon reasonable request.

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Funding

This work was supported by intramural grants from Augusta University awarded to A.A.E. and B.B and grant from the Egyptian Cultural Affairs and Missions Sector (Cairo, Egypt) in cooperation with the Egyptian Cultural and Educational Bureau (Washington DC, USA) awarded to K.M.S.

Author information

Authors and Affiliations

  1. Department of Oral Biology and Diagnostic Sciences, Dental College of Georgia, Augusta University, 1450 Laney Walker Blvd, CL2126, Augusta, GA, 30912, USA

    Karim M. Saad, Évila Lopes Salles, Sahar Emami Naeini, Babak Baban & Ahmed A. Elmarakby

  2. Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt

    Karim M. Saad, Marwa E. Abdelmageed, Rania R. Abdelaziz, Ghada M. Suddek & Ahmed A. Elmarakby

Authors
  1. Karim M. Saad
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  2. Évila Lopes Salles
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  3. Sahar Emami Naeini
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  4. Babak Baban
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  5. Marwa E. Abdelmageed
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  6. Rania R. Abdelaziz
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  7. Ghada M. Suddek
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  8. Ahmed A. Elmarakby
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Contributions

KMS contributed to mice surgical operations, biological sample collection, measurements, data analysis and manuscript drafting. ELS and SEN contributed to US Doppler measurements, biological sample collection and manuscript review. GMS, MEA, RRA and BB contributed to work conceptualization and manuscript review. AE contributed to experimental design, data analysis, manuscript drafting and review. All authors approved the final version of the manuscript.

Corresponding author

Correspondence to Ahmed A. Elmarakby.

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Saad, K.M., Salles, É.L., Naeini, S.E. et al. Reno-protective effect of protocatechuic acid is independent of sex-related differences in murine model of UUO-induced kidney injury. Pharmacol. Rep 76, 98–111 (2024). https://doi.org/10.1007/s43440-023-00565-2

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  • DOI: https://doi.org/10.1007/s43440-023-00565-2

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