direct-drug-delivery-to-kidney-via-the-renal-artery

Direct Drug Delivery to Kidney via the Renal Artery

There is a need for directed injections to enable increased and specific renal exposure for efficient evaluation of drug targets in the renal research ...

BioPharmaceuticals R&D

There is a need for improved animal models that better translate to human kidney disease to predict outcome of pharmacological effects in the patient. The diabetic BTBR mouse model mimics key features of early diabetic nephropathy in humans, but with chronic injury limited to glomeruli. To explore if we could induce an accelerated and more advanced disease phenotype that closer translates to human disease, we challenged BTBR mice with a high-protein diet (HPD; 30%) and followed the progression of metabolic and renal changes up to 20 wk of age. Animals on the HPD showed enhanced metabolic derangements, evidenced by further increased levels of glucose, HbA, cholesterol, and alanine aminotransferase. The urinary albumin-to-creatinine ratio was markedly increased with a 53-fold change compared with lean controls, whereas BTBR mice on the standard diet only presented an 8-fold change. HPD resulted in more advanced mesangial expansion already at 14 wk of age compared with BTBR mice on the standard diet and also aggravated glomerular pathology as well as interstitial fibrosis. Gene expression analysis revealed that HPD triggered expression of markers of fibrosis and inflammation in the kidney and increased oxidative stress markers in urine. This study showed that HPD significantly aggravated renal injury in BTBR mice by further advancing albuminuria, glomerular, and tubulointerstitial pathology by 20 wk of age. This mouse model offers closer translation to humans and enables exploration of new end points for pharmacological efficacy studies that also holds promise to shorten study length.

Ulrika Dahlqvist

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