Renal Proximal Tubule ACE2 Knockout Exacerbates Pregnancy Outcomes in a Mouse Model of Recovered Acute Kidney Injury

Background: Acute kidney injury (AKI) has been associated with long-term renal and cardiovascular disease after initial injury and apparent recovery. Emerging evidence suggests that recovered AKI may additionally adversely affect future reproductive and pregnancy outcomes. We recently observed that mouse dams with recovered AKI and normal pre-pregnancy renal and cardiovascular function developed renal fibrosis and proximal tubule dysfunction in subsequent pregnancy. Despite sufficient recovery time post-injury, AKI-affected dams exhibited lower glomerular filtration rates, elevated mean arterial pressure, and smaller fetoplacental ratios at term. Reduced maternal renal megalin was a critical finding as megalin is a ligand for several factors in the renin-angiotensin system (RAS). Therefore, we hypothesized that inhibiting angiotensin-converting enzyme 2 (ACE2), a key RAS component, would further impair renal response and pregnancy outcomes. Methods: Procedures were approved by institutional IACUC. Rhabdomyolysis was induced in proximal tubule-specific Cre-positive ACE2 knockout (PTACE2KO, Ace2flox/flox:PEPCKCre, n=3) and Cre-negative ACE2-expressing mice (n=4) on SV/129 background via intramuscular injection of 50% glycerol (8 mL/kg) and compared to PTACE2KO uninjured shams (n=3). Renal function was assessed 24 hours after injury or sham procedure via glomerular filtration rate (GFR; μL/min/100g body weight) quantification by transcutaneous FITC-sinistrin elimination and repeated 2 weeks later to ensure return to baseline levels, followed by timed matings with uninjured males. Following 2 days of acclimation, blood pressures were measured by tail cuff plethysmography on gestational day 16.5 (GD16.5, near term). Urine was collected for 24 hours in metabolic cages. On GD17.5, GFR was measured. In addition, fluorescence readings were used to calculate changes in blood volume during pregnancy using RStudio. Dams were then euthanized; maternal blood, kidney, and heart, placentas, and fetuses were weighed and collected for analysis. Statistics were assessed by ANOVA with Tukey posthoc. Results: At GD17.5, PTACE2KO AKI dams had significantly higher systolic (128.7 vs 165.5, p=0.03) and mean arterial (105.7 vs 132.2, p=0.05) pressures than Cre-negative AKI dams. GFR in dams with PTACE2KO and recovered AKI had 26% lower GFR than Cre-AKI dams (791.5 vs 1072 ul/min/100g body weight, p< 0.01); this was 43% lower compared to PTACE2KO uninjured dams (791.5 vs 1399, p< 0.001). A smaller fetoplacental ratio was also observed in PTACE2KO and AKI pregnancies compared to those without AKI (p< 0.05). More fetal reabsorptions were observed in PTACE2KO AKI pregnancies than in any other group (average 2/litter, p< 0.05). Blood volume expansion was less in dams with AKI than uninjured dams (p< 0.01). Kidneys and hearts from PTACE2KO dams with AKI were heavier than those from shams normalized to body weight (p< 0.05). Discussion: AKI poses reproductive and pregnancy risks long after initial apparent maternal recovery. Rhabdomyolysis is a particularly relevant form of AKI for this model as reproductive-age people are more likely to have this form of acute kidney injury and to survive such incidents. ACE2 function may be key to understanding renal dysfunction following AKI particularly in the setting of pregnancy. The failure of blood volume expansion and elevated blood pressure during pregnancy illustrates maternal cardiorenal dysfunction underscored by unmet fetoplacental demand. Identifying mechanisms and new therapeutic targets of renal dysfunction during pregnancy will improve maternal prenatal, gestational, and postnatal care. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.