Src Homology Phosphatase 2 Disruption in Podocytes Attenuates Markers of Aristolochic Acid 1-Induced Renal Injury, Inflammation, and Fibrosis in Mice

Aristolochic acid nephropathy (AAN) is a tubulointerstitial kidney disease caused by ingestion of aristolochic acids (AA). It is a global health concern, with no established disease-modifying therapy. Src homology phosphatase 2 (Shp2; encoded by Ptpn11) is a ubiquitously expressed protein tyrosine phosphatase that is implicated in renal development and function, but its contribution to AAN is unknown. Mice with podocyte-specific Shp2 disruption (Ptpn11fl/fl;Pod-Cre; KO) and controls (Ptpn11fl/fl) were subjected to weekly intraperitoneal injections of saline or aristolochic acid 1 (AA1, 5 mg/kg) for 4 consecutive weeks. Afterward, animals were sacrificed at 6 and 11 weeks. Renal Shp2 protein and immunofluorescence staining, including in glomeruli, were elevated following AA1 challenge. Relative to controls, KO mice exhibited attenuation of AA1-evoked changes in renal function indices, including kidney-to-body weight ratio, blood urea nitrogen, and urine albumin-to-creatinine ratio. Additionally, AA1-induced elevation in blood pressure was reduced in KO mice. At the molecular level, Shp2 deficiency was associated with significantly lower AA1-induced renal expression of inflammatory (Ccl2, Tnf) and fibrotic (Acta2, Col1a1) markers compared with controls. Histologically, AA1-induced renal interstitial collagen deposition, evaluated by picrosirius red staining, was significantly reduced in KO mice compared with controls. These findings indicate that podocyte Shp2 deficiency confers beneficial effects and attenuates AA1-induced renal injury, inflammation, and fibrosis, and identify Shp2 as a target in AAN.