In normal pregnancy, increased activities of the systemic RAS and sympathetic nerves result in sodium and water retention throughout the body, leading to plasma volume expansion 1. In the RAS, ACE2 degrades and converts vasoconstrictive Ang II into vasodilative Ang (1–7), thus exerting vasodilatory properties 11. According to recent human and animal studies, in addition to serum concentrations 27, placental and renal concentrations of ACE2 are also elevated during pregnancy 24,28, suggesting their direct effects on organ function. In the kidneys, ACE2 and Ang (1–7) expression during pregnancy were increased specifically within the proximal tubular cells, which then returned to the virgin levels in the postpartum period (Fig. 2A and B). Further, these changes were synchronized with changes in vascular tone observed during pregnancy (Fig. 1). Based on these results, the increased renal expression of ACE2 and Ang (1–7) in pregnancy was thought to be responsible for renal vasodilation, subsequently causing an increase in renal blood flow and the GFR (Fig. 3). Besides, as Ang (1–7) directly dilates the afferent arterioles in the glomeruli 29, it would bring about an additional increase in the GFR during pregnancy.
Patients with severe COVID-19 sometimes develop acute kidney injury (AKI) 30,31. Recent studies have reported the involvement of direct viral invasion, renal medullary hypoxia due to hypoperfusion, rhabdomyolysis, and microangiopathy secondary to a cytokine storm in this pathogenesis. Thus, the pathological features of AKI following COVID-19 infection are typically characterized by proximal tubular damage due to acute tubular necrosis or interstitial inflammation 30–32. Pregnancy is a risk factor for severe COVID-19 16, and pregnant women are prone to develop AKI following COVID-19 infection 17,18. Our results showed that the proximal tubular expression of ACE2 and TMPRSS2 was similarly enhanced during pregnancy (Fig. 2A and C); notably, their distribution was almost overlapped with that of AKI lesions following COVID-19 30–32. ACE2 and TMPRSS2 are transmembrane proteins that facilitate SARS-CoV-2 entry into cells, allowing the virus to stimulate pro-inflammatory cytokine production and induce organ injury 26. In chronic diseases, such as heart failure, chronic kidney disease, and chronic obstructive pulmonary disease, enhanced expression of these proteins in damaged organs results in the development of severe COVID-19 13–15. Therefore, enhanced proximal tubular expression of ACE2 and TMPRSS2 during pregnancy may be responsible for the development of AKI following COVID-19 in this condition (Fig. 3). Given this pathogenesis, the use of ACE2 inhibitors or soluble forms of ACE2 protein, which directly block the cellular entry of SARS-CoV-2 33–35, as well as the use of natural products that directly or indirectly modulate ACE2 activity 36 would be beneficial in preventing AKI in pregnant women.
In summary, in the kidneys of pregnant rats, in addition to renal arterioles and venules, glomerular capillaries are markedly dilated and the Bowman’s capsule is enlarged, indicating renal vasodilation. Immunohistochemistry demonstrated increased ACE2 and Ang (1–7) expression in the proximal renal tubules of pregnant rats. As these proteins exert vasodilatory properties, they are considered responsible for renal vasodilation and the subsequent increase in GFR during pregnancy. Further, the similarly distributed and enhanced expression of ACE2 and TMPRSS2 in the proximal tubules suggests their roles in AKI development following COVID-19 infection during pregnancy.