Renal Adaptation and Vulnerability: Unilateral Nephrectomy Affects Response to Crystalline Nephropathy

Background: Unilateral nephrectomy (UNx) is a surgical procedure that leads to compensatory changes in the remaining kidney, which may result in functional overload and increased vulnerability to further injury. However, the impact of UNx on the kidney’s response to secondary insults, such as crystalline nephropathy, warrants further investigation. This study aimed to investigate the functional and molecular responses in UNx mice, with or without sodium oxalate induced renal injury. Methods: Male C57BL/6J mice (n=31,eight-week-old) were assigned to four experimental groups: sham operated, UNx, sodium oxalate (NaOx; intraperitoneal injection of 9 mg/100g to induce nephrolithiasis,24 hours prior to euthanasia), and UNx plus NaOx treatment (UNx/NaOx). Forty-one days after surgery, and twenty-four hours before euthanasia, mice received their respective treatments and were housed in metabolic cages for renal function evaluation. After the 24-hour period, animals were anesthetized with isoflurane (0.8 L/min, 5% flow rate), and blood, urine, and the kidney were collected prior to euthanasia by exsanguination. Results: Six weeks after surgery, UNx animals revealed a significant increase in creatinine clearance (p<0.02), glomerular area (p<0.05), and mRNA expression of Mki-67 (p<0.03). They also showed elevated expression of fibrosis-related genes COL1A1 (p<0.04) and COL4A1 (p<0.01), as well as elevated protein expression of α-SMA (p<0.04) indicating early fibrotic remodeling. In contrast, UNx/NaOx led to a further increase in kidney weight (p<0.0001), glomerular area (p<0.0003), and plasma creatinine (p<0.03), suggesting a vulnerability of the remaining kidney, negatively affecting its response to NaOx-induced injury. Interestingly, both models of kidney injury showed increased tubule expression of Matrix Metalloproteinase 10 (MMP-10), suggesting a role for this endopeptidase in the response to kidney damage. However, its precise contribution to damage progression remains to be elucidated. Conclusion: Our data suggests that UNx may increase the vulnerability of the remaining kidney to additional stress and potentially to fibrosis progression. The upregulation of MMP-10 suggests it may play a role in the renal damage response. Further studies are needed to determine whether MMP-10 contributes to repair or promotes the progression of kidney fibrosis. Funding: Government Support – Non-U.S.